Directory UMM :Data Elmu:jurnal:B:Brain Research:Vol886.Issue1-2.Nov2000:

(1)

www.elsevier.com / locate / bres

Interactive report

Nitric oxide, impulse activity, and neurotrophins in visual system

development

*

R. Ranney Mize , Fu-Sun Lo

Department of Cell Biology and Anatomy and The Neuroscience Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112,

USA

Accepted 31 July 2000

Abstract

Topographic refinement of synaptic connections within the developing visual system involves a variety of molecules which interact with impulse activity in order to produce the precise retinotopic maps found in the adult brain. Nitric oxide (NO) has been implicated in this process, as have various growth factors. Within the subcortical visual system, we have recently shown that nitric oxide contributes to pathway refinement in the superior colliculus (SC). Long-term potentiation (LTP) and long-term depression (LTD) are also expressed in SC during the time that this pathway undergoes refinement. The role of NO has been demonstrated by showing that refinement of ipsilateral fibers in the retinocollicular pathway is significantly delayed in gene knockout mice in which both the endothelial and neuronal

isoforms of nitric oxide synthase (NOS) have been disrupted. The effect also depends upon Ca channels because refinement of both the

ipsilateral retinocollicular and retinogeniculate pathways is disrupted in genetic mutants in which theb3 subunit of the Ca channel has been deleted. LTD may also be involved in this process, because the time course of its expression correlates with that of pathway

refinement and LTD magnitude is depressed by nitrendipine, an L-type Ca channel blocker. LTP is also expressed during early postnatal development in the LGN and SC and may contribute to synaptic stabilization. The role of neurotrophins in pathway refinement in the visual system is also reviewed.  2000 Elsevier Science B.V. All rights reserved.

Theme: Development and regeneration

Topic: Visual system

Keywords: Pattern formation; Synapse specificity; Growth factor; Superior colliculus; Lateral geniculate nucleus; Visual cortex

1. Introduction process does depend upon impulse activity and can be

influenced by patterned visual experience as well. These The major visual centers of the mammalian brain later stages of refinement are also mediated by various contain precise retinotopic maps which represent an image growth factors and other signals, the result being the of the external world. These maps are established gradually formation of very precise synaptic connections that func-during pre- and postnatal development. The process occurs tion in the adult. These stages of visual system develop-in stages. Early develop-in development a coarse map is formed develop-in ment have been reviewed extensively which the major axes of representation between the retina [10,17,70,78,86,139].

and its subcortical targets are established. This stage is The later stages of synaptic plasticity which result in activity independent, but involves a variety of molecules precise matching of presynaptic axons with post-synaptic that control axon guidance. These coarse maps are further neurons are thought to involve one or more retrograde refined at later stages of development, and this later signals which ‘inform’ the presynaptic terminal that it has established an appropriate connection with the postsynaptic neuron. Although a retrograde message is probably re-1

Published on the World Wide Web on 16 August 2000.

quired for this process [8,14,147], candidates for this *Corresponding author. Tel.:11-504-568-4012 or 568-4011; fax:

11-message have only recently been identified. Cellular 504-568-4392.

(2)

also recently been shown to occur during the later stages of postnatal development the projections from the retina to pathway refinement in visual system development. This the SC are exuberant in that both the ipsilateral and article focuses upon several retrograde signals, notably contralateral retinal pathways overlap extensively with nitric oxide and the neurotrophins, that contribute to many axons misdirected to inappropriate targets pathway refinement in the visual pathways. We also review [38,42,68,69,95,117,141,143]. Both projections sub-evidence that long term potentiation (LTP) and long term sequently undergo refinement in which incorrectly targeted depression (LTD) are involved in the synaptic refinement axons disappear either due to retraction of axon branches

process. or to elimination of the parent axon. This process of

refinement is thought to be mediated by the NMDA receptor in both rodent SC [142] and in the optic tectum of

2. Nitric oxide and pathway refinement in the lower vertebrates [35,36].

developing visual system This refinement is also partially mediated by NO. Thus,

NOS is expressed maximally in neurons within the re-Nitric oxide (NO), a free radical gas, is well-established tinorecipient layer of rodent SC (superficial gray layer as a neuromodulator in brain [22–24,50,65,66,156]. As a (SGL)) between the ages of P4–P21, the time during gas, NO can move rapidly across the plasma membrane in which the retinocollicular pathway is undergoing massive both anterograde and retrograde directions [94,156] and refinement. Neurons containing NOs synthetic enzyme, can therefore signal back to presynaptic terminals that NOS, increase in number 2–3 fold between P1 and P21, activity has occurred in a postsynaptic neuron [63,114]. and then decrease in number in the adult (Fig. 1A,B), as This process is thought to involve a sequence of steps. In demonstrated using both an antibody directed against the post-synaptic neuron the events that result in NO nNOS and by use of the histochemical marker NADPH

release include Ca influx through the NMDA receptor diaphorase. Retinorecipient neurons expressing NOS in the which triggers a calcium-calmodulin dependent increase in SGL have a variety of morphologies, including both nitric oxide synthase (NOS) which in return results in excitatory and inhibitory cell types (Fig. 1C,D) [40,112]. production and release of nitric oxide (NO). Presynaptical- Consistent with the time-course of NOS expression, ly, NO can activate a guanylate cyclase-cGMP second refinement of the ipsilateral retinocollicular pathway is messenger system in the presynaptic terminal which can significantly delayed in gene knockout mice in which the lead to an increase in the release of neurotransmitter endothelial and neuronal isoforms of NOS have been [21,65,107,108]. There are, however, a variety of other disrupted (e,nNOS mutants, [79]). In SC, this disruption signal transduction pathways implicated in this process, results in an expanded ipsilateral retinocollicular projection and the release and action of NO is complex and incom- which remains more widely distributed across the superfi-pletely understood [51]. cial layers of SC of e,nNOS knockout mice compared to NO was shown to be involved in some forms of synaptic normal mice from ages P9 until at least P42 [113,159,160]. plasticity, such as long term potentiation and long term Fig. 2 illustrates this effect where it can be seen that depression, beginning nearly ten years ago [3,16,75,116]. multiple patches of labeled fibers are distributed more Its role in pathway refinement in the developing brain, widely in both the rostrocaudal and mediolateral axes of however, has only recently been established. The phenom- SC than in normal C57 / BL-6 controls (Fig. 2A,B). enon has been best studied in the visual system. In 1994 Multiple patches of labeled fibers are seen in the rostral Wu et al. [157] first reported that NO could alter refine- lateral SC and also in the caudal medial SC in the double ment in the chick ipsilateral retinotectal pathway by knockout (Fig. 2B, arrows). Significant differences in the showing that the pathway, which is normally transient and cross-sectional area occupied by these labeled fibers have eliminated during embryogenesis, is partially spared after been found when measured in knockout and C57 / BL6 inhibition of NOS, NO’s synthetic enzyme [157,158]. This mice at two ages: P15 [160] and P28 (Fig. 2C,D and 159). process is NMDA dependent [58] and may also depend Although there is a significant delay in refinement, the upon interaction with the growth factor BDNF (see below, ipsilateral retinocollicular pathway does eventually retract.

[59]). The pathway begins to refine in the e,nNOS knockout as

Development of the retinogeniculate pathway is also early as P9 and is like that of normals by adulthood altered by inhibition of NOS. Thus, intraperitoneal in- [159,160].

jections of n-v-nitro-l-arginine, a NOS inhibitor, disrupts Recently, Vercelli et al. [152] have confirmed this effect the segregation of the ‘on’ and ‘off’ sublaminae of the by showing that the density and distribution of retinocol-ferret lateral geniculate nucleus [44–48]. This effect is also licular axons is expanded in rats treated for 4–6 weeks dependent upon the NMDA receptor [71] and upon with a NOS inhibitor. Branch length and numbers of impulse activity in the retinal afferents [45]. More recently, synaptic boutons are increased in the inhibited rats [152], we have shown that development of the ipsilateral re- suggesting that the effect involves not only the distribution tinocollicular pathway in the mammalian superior col- of fibers but also the density of branches and synapses. A liculus (SC) also depends in part upon NO. Early in similar effect is seen in the rodent LGN where there is an

(3)

Fig. 1. Distribution of nitric oxide in the developing rodent superior colliculus. (A) Computer plots illustrating the distribution of NO containing neurons within the mouse SC at varying ages after birth. Neurons were labeled by an antibody to nNOS. Onset of expression in the retinorecipient layers occurs by P5, with the numbers of neurons increasing thereafter, reaching a peak at P21. There is a decrease in the adult. Modified from Cork et al. [40]. (B) Histogram showing the ventral to dorsal progression in development of nNOS immunoreactivity in the rodent SC. Note that the peak distribution within the superficial gray layer (SGL) is at P21. There is a substantial decrease in the numbers of labeled neurons in all layers in the adult. Modified from Cork et al. [40]. (C,D) Micrographs showing the dense distribution of NO containing neurons within the rodent SC at P14 and P21. Neurons are labeled NADPHd. There is a very dense distribution of labeled neurons within the superficial gray layer (SGL) at both ages. There are few labeled neurons within the optic layer (OL), but some labeled neurons are also scattered within the deep layers (asterisks). Modified from Scheiner and Mize [131] and Mize et al. [112].

(4)

Fig. 2. Development of the retinocollicular pathway in normal and e,nNOS double knockout mice. (A,B) Stacked sections of SC showing the rostral (bottom) to caudal (top) distribution of the ipsilateral (left) and contralateral (right) retinocollicular pathways in normal (A) and (B) e,nNOS double knockout mice at age P21. Note the more extensive distribution of fibers with multiple patches of label seen in more lateral and caudal regions of SC (arrows in the e,nNos knockouts). Modified from Wu et al. [160]. (C,D) Histograms showing the area of labeling of the ipsilateral retinocollicular pathway in e,nNOS double knockout mice (C) and normal C57 / BL-6 mice (D) at age P28. The area occupied by the ipsilateral patches is expressed as a percent of the contralateral label found in the same section. Significant differences were observed at the 500–600mm intervals (P,0.005) and at the 800–900 and 1100mm intervals (P,0.05). Modified from Wu et al. [159].

increase in distribution and density of ipsilateral retinal below and [56,73,90,91]) do not depend upon NO [73,91]. fibers which expand into the territory of the contralateral Thus, there is consistent anatomical and physiological representation of that nucleus [152]. There is thus evidence evidence that NO is not involved in neonatal cortical from several laboratories showing that nitric oxide medi- plasticity.

ates pathway refinement in both the retinogeniculate and NO inhibition also fails to modify refinement in several retinocollicular pathways of some mammals. other visual system pathways. Thus, chronic application of NO appears not to mediate pathway refinement in some an NO inhibitor does not disrupt the formation of eye other regions of the brain. For example, inhibition of NOS specific stripes that occurs in the optic tectum of three-does not block the formation of ocular dominance columns eyed frogs [124] even though NOS is expressed in tectal in ferret visual cortex even though NO is expressed in neurons during the formation of these stripes and applica-visual cortical subplate neurons during the time that these tion of NO donors results in growth cone collapse and columns are established [61]. NOS inhibition also fails to retraction of retinal ganglion cell axons in this species block the shift in ocular dominance that occurs in primary [123]. Finally, inhibition of NOS does not block the visual cortex neurons after monocular deprivation, pro- segregation of retinal fibers into ipsilateral and contralater-viding further evidence that NO does not mediate synaptic al laminae of the ferret LGN [48]. Thus, NO has an effect plasticity of ocular dominance columns [122,129]. In on only some visual system pathways and only in certain addition, cellular correlates of synaptic plasticity (LTP, species, and the factors which determine whether NO LTD) which are present in developing visual cortex (see mediates refinement are as yet incompletely understood.

(5)

3. The role of impulse activity in visual pathway activity in the nerve terminal. Inhibitors of NOS block this

refinement decrease in amplitude, showing that the effect is NO

specific. The source of NO is thought to be from the Impulse activity in presynaptic afferents and post-synap- post-synaptic muscle because intracellular injection of the tic neurons has long been known to be a factor contribut- NOS inhibitor into the myocyte also blocks the effect. This ing to the formation of precise retinotopic connections in evidence shows directly that NO release can produce brain [70,86,139]. The role of patterned vision in forming depression of presynaptic activity in developing synapses. connections within the visual cortex was established over The effect of NO appears to be specific to synapses with 40 years ago by showing that deprivation of vision in one low spontaneous activity because active nerve terminals eye diminishes the influence of that eye so that only the are less affected by application of NO donors [153]. non-deprived eye can drive cortical neurons. Ocular domi- Other evidence suggests that the action of NO in nance columns in visual cortex which represent the non- pathway refinement may not require or even be related to deprived eye were also shown to expand in size in order to impulse activity. A number of studies have shown that NO favor the eye with normal vision (see [81], for review). donors produce arrest and retraction of growth cones and More recently, it was discovered that spontaneous impulse filipoidia in in vitro models in which impulse activity is activity in the retina can also influence the formation of largely absent [59,67,76,77,151,123]. These studies sup-synaptic connections before eye opening. This activity port the conclusion that NO serves as a repellant molecule arises from spontaneous discharges which produce waves that can promote coarse axon arbor retraction that is of correlated electrical activity in neighboring retinal unrelated to patterns of impulse activity (see [124]). Thus, ganglion cells [62,109,139]. This correlated activity in the link between impulse activity and NO mediated adjacent regions of retina leads to synaptic strengthening in pathway refinement is based largely upon indirect evidence presynaptic fibers representing a similar region of retina in which activity has been blocked by TTX but not when compared with uncorrelated activity in fibers from manipulated or measured directly at the synapse. A more other retinal sites [15,109]. direct approach to the study of this relationship is an

This spontaneous impulse activity has been shown to be important future direction for research on this topic. important in the formation of ocular dominance columns in One promising approach is to artificially induce pre- and visual cortex [32,148] and in the segregation of retinal post-synaptic activity in competing pathways using electri-axons into eye specific layers in the LGN [140]. In both cal stimulation and whole cell recording in a slice prepara-structures, injections of TTX, a sodium channel blocker, tion. This technique permits one to examine potentiation or blocks formation of normal patterned connections, pre- depression of synaptic transmission and how it is modified sumably due to the imbalance in impulse activity in the by pairing stimuli applied to one or both pathways. Recent two eyes. The pattern of activity is also important, since studies by Poo [161] have shown that the temporal order of artificially induced synchronous activity in the ipsilateral activation of synapses in convergent pathways can de-and contralateral optic nerves can also block formation of termine whether a synaptic response is strengthened or ocular dominance columns while asynchronous activity depressed in individual neurons. In the frog retinotectal sharpens these columns [149]. Activity patterns are also system, repetitive stimulation of one region of the retina important in refining the retinotectal pathway in lower just prior to spiking of a postsynaptic neuron potentiates vertebrates [25,121,132–134]. subsequent responses of that neuron to stimulation. Pairing A relationship between impulse activity and the action this stimulus with a weak stimulus to another region of the of NO in development was predicted explicitly by Gally et retina, which also activates the neuron via a convergent al. [63,114]. They showed in modeling experiments that synapse, produces a depression in the response to the NO could alter synaptic efficacy such that synapses whose second stimulus, but only when the pairing falls within a presynaptic activity is correlated with action potentials in critical time frame [161]. Thus, both the temporal sequenc-the postsynaptic neuron would be strengsequenc-thened by sequenc-the ing of impulse activity in the convergent inputs and the release of NO while those with uncorrelated activity would level of spiking in the post-synaptic neuron determine be weakened. Impulse activity has subsequently been whether convergent synapses will be potentiated or de-shown to contribute to NO mediated pathway refinement in pressed [161].

several experiments. Thus, TTX injection into one eye We have recently developed an in vitro brainstem blocks the segregation of the on and off sublaminae of the preparation which also allows us to study directly how the ferret LGN [45] in a manner similar to that of NOS timing and amount of impulse activity in the ipsilateral and inhibition [47]. The role of NO in activity dependent contralateral retinocollicular pathways affects the efficacy synaptic depression has also been shown directly in nerve of individual synapses in the rodent SC. This preparation is muscle cultures [153]. In this preparation NO donors an isolated brainstem that includes the midbrain, dien-decrease the amplitude of evoked presynaptic currents cephalon (thalamus), and also the optic tracts, optic when the myocyte is depolarized in order to artificially chiasm, and optic nerves that are intact and remain produce activity which is uncorrelated with presynaptic functionally connected to the eye (Fig. 3A). The ipsilateral

(6)

synaptic field potentials (Fig. 3B,C), or extracellular action potentials (Fig. 3D,E), or even intracellular post-synaptic responses from individual cells in which the synaptic circuitry remains intact. Preliminary data shows that we can elicit responses from both pathways (Fig. 3B,C). Spontaneous activity can also be recorded from single cells in SC (Fig. 3F). This activity sometimes displays a rhythmicity suggesting that the retina produces sponta-neous retinal waves in this preparation. We do not yet know how NO will modulate these responses, but NO does affect LTD in a similar preparation (see below).

4. NO Mediated pathway refinement and LTP/ LTD

It has been proposed that the cellular mechanisms which mediate weakening and strengthening of synapses during development are long term depression (LTD) and long term potentiation (LTP) [8,10,14,110,136,144]. LTP is a long-lasting potentiation of an evoked response that occurs following application of a tetanus or other event which enhances the long term efficacy of synaptic transmission. LTD is a long lasting depression that reduces the long term efficacy of synaptic transmission (see [9,103] for recent review). LTP and LTD have been shown to be mechanisms underlying associative learning in the adult brain, and there is a body of evidence showing that both LTP and LTD are mediated by NO in some but not all experimental con-ditions [3,16,49,75,84,96–98,116,136,146]. Evidence that LTP and LTD play a role in pathway refinement is more recent. Hypothetically, LTP in developing brain should lead to strengthening and stabilization of synapses by potentiating synaptic transmission while LTD should lead to weakening and eventual retraction of synapses by depressing the synapse [8,10,70]. Weakening of the synapse via LTD would occur because activity in the depressed afferent is not correlated with that of the postsynaptic neuron or occurs at a time when the post-synaptic neuron is at less than a threshold membrane potential; and conversely, strengthening of the synapse via LTP would occur because activity in the potentiated Fig. 3. Isolated brainstem preparation used for physiology experiments.

afferent is correlated with that of the postsynaptic neuron (A) The rat isolated brainstem includes the inferior colliculus (IC),

or occurs at a time when the postsynaptic neuron is at superior colliculus (SC), thalamus (TH) and associated diencephalic

structures. The optic tracts, optic nerves (ON), and eyes are also left _{higher than a threshold membrane potential [10,14]. The} intact in some preparations. Either or both optic nerves can be stimulated. _{level of calcium influx is likely to be one factor which} Field potential, extracellular, and intracellular recordings are made from

determines whether LTP or LTD will be induced [4,102]. the SC or LGN. (B–F) Recordings from the SC of this preparation. (B,C)

Despite the appeal of this idea, there is to date only Field potentials generated by stimulation of the contralateral (B) or

limited evidence to support a relationship between LTP, ipsilateral (C) ON. (D,E) Evoked extracellular action potentials can also

be recorded from single cells in this preparation. (F) Spontaneous activity _{LTD, and pathway refinement ([39], for review). LTP has} is also present in SC neurons, confirming that the retina is functional. _{been shown to be present in synapses during the period of} barrel field plasticity in somatosensory cortex [43] and and contralateral optic nerves can be stimulated separately during the period of ocular dominance plasticity in visual or together in order to generate postsynaptic responses cortex [11,85,87,91,119]. LTD has also been shown to within the SC (Fig. 3B–F). The preparation is thus ideal occur in neonatal somatosensory [60] and visual cortex for studying the interaction between synaptic inputs be- [56,90]. These forms of LTP and LTD are for the most cause the inputs can be stimulated while recording post- part homosynaptic, NMDA mediated, and age dependent

(7)

[43,56,60,89–92]. Thus, for example, LTP can be induced stimulation induces LTD, irrespective of frequency (Fig. in layer III neurons of visual cortex only at ages which 4A). LTD induced by both low and high frequency stimuli roughly match the critical period for ocular dominance reduces the amplitude of both excitatory field potentials formation, and it can be prolonged by dark-rearing and is and excitatory post-synaptic currents (EPSCs) by approxi-therefore visually mediated [89,91]. This LTP is also mately 40%. This LTD is developmentally regulated. It NMDA dependent but is not affected by an antagonist to can occur as early as P0–P3 (Fig. 4B) and the magnitude NOS [89]. LTD has also been induced in developing visual of the depression is maximal from P0–P9 and then cortex [56,127,130,137]. This synaptic depression is also decreases in older animals (Fig. 4B). This form of neonatal sometimes NMDA dependent [130] and is also regulated LTD does not depend upon the NMDA receptor because by GABA receptors [56]. D-APV does not block it (Fig. 4C). Induction is also We have now demonstrated that both long-term depres- independent of GABAa receptor function because bicucul-sion (LTD) and long-term potentiation (LTP) can also be line also fails to block it. Perinatal LTD is also in-induced in perinatal rodent SC [99,100]. Both low (LF) dependent of Group I, II mGLUr receptors because neither and high frequency (HF) tetanic stimulation (1 Hz or 50 agonists nor antagonists of these receptors effect LTD Hz) of the optic tract can induce LTP and LTD in the SC amplitude [111]. It is, however, mediated by L-type of an isolated brainstem (Fig. 4A) as early as P0. Low calcium channels because it can be partially blocked by

intensity stimulation induces LTP while high intensity nitrendipine, an L-type Ca channel blocker (Fig. 4D)

Fig. 4. LTD and LTP in developing rodent superior colliculus (A) Response of SC to high frequency tetanic stimulation. The field potential recorded from the SC of the isolated brainstem can be either potentiated (open circles) or depressed (black circles), depending upon the intensity of stimulation. The effect is frequency independent. The change in field potential induced by the tetanus is long term (.90 min), showing that the change in synaptic transmission is like that of LTP and LTD. (B) Histogram showing that LTD is down-regulated during development. The magnitude of depression of the field potential produced by a high frequency stimulus declines with age. The differences in amplitude in rats aged P0–P9 vs. those aged P10–P25 is statistically significant (P,0.05). (C) LTD is NMDA independent. Application of D-APV (100mM) does not alter the depression of the amplitude of the field potential

induced by an HF tetanus. (D) LTD is partially dependent upon activation of L-type Ca channels. The depression of the field potential amplitude induced 21

by tetanus is less after application of 10mM nitrendipine, an L-type Ca channel blocker, compared to that induced by tetanus in control isolated brainstem. (B–D) modified from Lo and Mize [100].

(8)

[99,100]. The time course of onset and expression of LTD e,nNOS deficient mutants. However, there is a progressive

during development, its Ca channel dependence, and its decline in field potential amplitude beyond 30 min after NMDA independence are consistent with it playing a role application of the drug (Fig. 5B), which suggests that some in the induction of ipsilateral retinocollicular refinement of the effect may be due to damage to the neuron. Thus,

(see below). our preliminary evidence on the role of NO in LTD is

We are as yet uncertain whether LTD in neonatal SC is mixed, and further experiments must be performed. mediated by NO. LTD magnitude is depressed in some Recent studies of HF LTD show that both nitric oxide

e,nNOS double knockout mice when compared to C57 / and the L-type Ca channel also mediate this event in BL-6 controls (Fig. 5A); however, the reduction in mag- other brain structures. In hippocampus and striatum, HF nitude of LTD is not seen in all e,nNOS mutants at all LTD, which is found only in developing tissue, is mediated

ages, and variability in LTD amplitude from animal to by L-type Ca channels but not by NMDA receptors animal may in part explain the variable results. SNP, an [7,29,33,55]. In striatum, HF LTD can also be blocked by NO donor, greatly enhances LTD when applied to the NO synthase inhibitors, and is probably expressed pre-isolated brainstem of e,nNOS double knockout mice (Fig. synaptically because there is a decrease in the probability 5B), which is evidence that LTD can be rescued in of neurotransmitter release as measured by paired pulse facilitation [33]. HF LTD has also been reported in visual cortex, where it is mGLUr but not NMDA dependent (see [4], for reviews; [5,6]). Thus, there is growing evidence that LTD is present in neonatal tissue and that its charac-teristics differ depending upon the structure involved.

We have also been able to induce LTP in the developing rodent SC (Fig. 4A). This LTP can also be induced by high frequency tetanus (50 Hz) or low frequency (1 Hz) stimulation, and it appears in SC tissue as early as P1. The average LTP amplitude in rats aged P1–P13 is 46.560.7% (mean6S.E.) above baseline control (Fig. 4A). We do not yet know for certain whether this type of LTP is NMDA mediated. However, we do know that both NMDA and non-NMDA glutamate receptors are functional during the first week after birth in rodent SC. Thus, OT stimulation at moderate intensity between the ages of P1–P13 always evokes intracellular EPSPs which have both early and late components. The late component is mediated by the NMDA receptor since application of APV blocks this component (Fig. 6A). The early component is likely mediated by non-NMDA glutamate receptors. GABAa mediated IPSPs are also present in neonatal SC by P3 because application of bicuculline, a GABAa receptor antagonist, prolongs the excitatory postsynaptic potential that is masked by an IPSP (Fig. 6B). Strong stimulation of OT also evokes a sustained depolarizing potential (plateau

potential, Fig. 6C, trace 1) that is mediated by L-type Ca channels (Fig. 6C, trace 2). This may account for why high

intensity tetanus induces L-type Ca channel mediated LTD. LTD and LTP have also been recorded in the rodent lateral geniculate nucleus by our own and other lab-Fig. 5. Nitric oxide dependent effects on LTD. (A) LTD magnitude is _{oratories. As is the case in SC, LTD in the LGN is}

reduced in e,nNOS double knockout mice. The magnitude of LTD _{mediated in part by the L-type Ca} _{channel, is only} induced by an HF tetanus is less in the SC of mice in which the

partially NMDA dependent, and is present shortly after endothelial and neuronal isoforms of NOS have been disrupted than in

birth [162]. normal C57 / BL-6 mice. (B) SNP, an NO donor, markedly enhances LTD

of e,nNOS double-knockout mice. Application of 0.5 mM SNP prior to and during HF tetanus increases the magnitude of LTD (approx. 40% of

control) compared to LTD amplitude induced by tetanus without drug. _{5. Pathway refinement and calcium channel function} SNP alone decreases the amplitude of the field potential beyond 30 min,

suggesting that the late effects of the drug may be due to damage to the

The results reported above have shown that refinement cell. All recordings taken from the SC of the isolated brainstem

(9)

Fig. 6. Presence of NMDA and GABAa receptors and L-type Ca channels in rat neonatal SC. (A) NMDA receptor response. A moderate stimulus applied to OT of P1 rat elicits an excitatory post-synaptic potential (EPSP), consisting of a short and long duration component (trace 1). Application of D-aminophosphonovalerate (APV), an NMDA antagonist, blocks the late component (trace 2). (B) GABAa receptor response. Application of bicuculline, a GABAa receptor antagonist, in P3 rat can prolong the EPSP (trace 2) which is masked by a GABAa receptor mediated IPSP (trace 1). (C) Strong stimulation of OT can also induce a long-lasting plateau potential in neonatal SC neurons (trace 1). This plateau potential is blocked by application of 10

mM nitrendipine, an L-type Ca channel blocker (trace 2). (C) modified from Lo and Mize [99].

upon NO because the refinement is delayed in e,nNOS nels. We have now shown that this in fact occurs. The double knockout mutants [159,160]. LTD can also be refinement of both the ipsilateral retinocollicular and recorded in rodent SC during this period of postnatal retinogeniculate pathways are delayed in mice which lack development, and we have pilot data showing that it may the gene for the voltage gated calcium channelb3 subunit also be mediated by NO. It is also dependent upon the (CC-KO mice). L-type calcium channel currents are

re-21

L-type Ca channel, because the magnitude of LTD is duced 60% in these homozygous knockouts [115].

significantly reduced by an L-type Ca channel blocker Fig. 7 shows the distribution of retinal fibers in the SC [100]. The possible link between pathway refinement and of both wild-type and CC-KO knockout mice at P15. In LTD would be further established if it could be shown that these examples the ipsilateral pathway is much more the refinement of the ipsilateral retinocollicular pathway is extensive in distribution in the CC-KO knockout than in

(10)

Fig. 7. Development of the retinocollicular pathway in normal and Ca channelb3 subunit knockout mice. (A,B) Stacked sections of SC showing the 21

rostral (bottom) to caudal (top) distribution of the ipsilateral (right) and contralateral (left) retinocollicular pathways in wild-type (A) and Ca channel b3 subunit knockout mice (B) at P15. Note the more extensive distribution in caudal sections in the knockout animal. Modified from Cork et al. [41]. (C)

2 21

Histogram showing the area (mm ) occupied by the ipsilateral retinocollicular pathway in wild type and Ca channelb3 subunit knockout mice. Note that there is a dramatic difference in the amount of label in all 10 100mm intervals caudal to the rostral pole of SC. (D) Coronal section of mouse SC at age

P15 showing the distribution of neurons within the superficial gray layer (SGL) labeled by an antibody to the L-type Ca channel. These neurons are located within the retinorecipient zone of SC.

of tissue occupied by the label are considerable, even 6. Neurotrophins and their interaction with nitric

within the rostral SC (Fig. 7C). This result is consistent oxide in pathway refinement 21

with findings that L-type Ca channel immunoreactivity

is expressed in retinorecipient neurons in mouse SC during One reason that NO is such an appealing candidate as a the period of pathway refinement (Fig. 7D). There is also retrograde signal in synaptic plasticity is that its diffusion less segregation and greater expansion of the ipsilateral properties as a gas allow it to act in a time-frame of retinogeniculate pathway in CC-KO mice. This expansion milliseconds to seconds and to spread beyond a single includes a larger patch of label within the ipsilateral synapse in order to influence a volume of surrounding domain of the LGN with many ipsilateral fibers extending tissue [57,94,156]. NO can thus influence multiple beyond the domain (Fig. 8A). The contralateral re- synapses on a time scale in which synaptic transmission tinogeniculate pathway also invades the ipsilateral re- operates. However, other candidates with properties that tinogeniculate fiber domain to a greater extent in CC-KO likely operate on other time scales have also been proposed compared to wild type mice (Fig. 8B,D). Our data thus as retrograde messengers in synaptic plasticity, notably the

show that down-regulation of voltage gated Ca channels neurotrophins [17,106,150, for reviews]. The neurotrophins in the CC-KO mutants can affect pathway refinement in include nerve growth factor (NGF), brain-deprived neuro-the SC to a degree similar to or greater than that seen in trophic factor (BDNF), and the neurotrophins NT-3 and e,nNOS knockouts; and it can also delay refinement of NT4 / 5, each of which binds to specific tyrosine kinase both the contralateral and ipsilateral retinogeniculate path- receptors (TrkA, TrkB, TrkC) [18]. Some of these are ways in the LGN. well-established as target-derived retrograde trophic factors

(11)

Fig. 8. Distribution of ipsilateral retinocollicular pathway label in the lateral geniculate nucleus (LGN) of wild type and Ca channelb3 knockout mice at P15. (A,C) Ipsilateral LGN in knockout (A) and wild type (C) mice. Note that the ipsilateral ‘patch’ of label in the knockout is expanded relative to that of the normal mice. (B,D) Contralateral LGN in knockout (B) and wild type (D) mice. The contralateral fibers invade the ipsilateral ‘patch’ to a much greater extent in the knockout. Modified from Cork et al. [41].

in the peripheral nervous system [18,118,145]. More been shown to be developmentally regulated. Thus, there is recently, the neurotrophins have also been implicated as an increase in expression of NGF, BDNF and NT-3 retrograde signals in visual system plasticity that occurs mRNAs in the occipital cortex of rats during the first three during development. weeks after birth [31,135]. The TrkB receptor is also The most extensive work to date has been in visual expressed during postnatal development in ferret visual cortex. Most of the neurotrophins and their associated Trk cortex [27] where TrkB antibody immunoreactivity in-receptors are expressed in visual cortex and some have creases in layers III and V during the critical period of

(12)

ocular dominance plasticity [27]. BDNF antibody immuno- identifies two factors which can interact in the process of reactivity also peaks during the critical period of cortical stabilizing or eliminating axonal connections. In this plasticity in rats where it is preferentially distributed in schema, BDNF promotes axonal growth and growth cone layers II–III and V–VI [128]. Levels of neurotrophins are extension while NO promotes axon retraction and elimina-also regulated by visual input. Thus, monocular deprivation. The two when acting together can stabilize synapses tion decreases both BDNF mRNA and BDNF immuno- by preventing further growth or retraction. It remains to be reactivity in rat visual cortex [20,128] while dark rearing determined whether this mechanism is mediated by im-decreases BDNF but increases NGF [135]. Thus, many of pulse activity.

the neurotrophins and their associated receptors are ex- The actions of the neurotrophins in regulating pathway pressed at the proper sites and at the appropriate times in refinement are clearly activity dependent in other visual order to be able to mediate synaptic plasticity in visual system structures. A series of pioneering studies by Maffei cortex, and they can be regulated by visual stimulation, et al. showed that intraventricular infusion of NGF (1) which is further evidence that they play a role in activity prevents the shift in ocular dominance that occurs physio-dependent refinement. logically in single cells of rat visual cortex after monocular Application of exogenous neurotrophins and / or their deprivation (MD) [12,101]; (2) prevents loss of acuity in receptors also influence neuronal and axonal growth in the deprived eye [52]; and 3) reduces the anatomical developing visual cortex. As an example, McAllister et al. shrinkage of neurons that normally occurs in the deprived [104–106] have demonstrated that several classes of laminae of the LGN [53]. A similar effect has been found neurotrophins can modulate dendritic length and branching in kitten visual cortex where intraventricular administration in pyramidal neurons of ferret striate cortex [106, for of NGF also reduces the shift in cortical ocular dominance review]. The effect is different for different neurotrophins. and cell shrinkage in deprived LGN laminae [30]. By BDNF increases the length of the basal dendrites of contrast, implanting anti-NGF producing cells into the pyramidal neurons in layer IV while NT-4 effects those in ventricles of rats prolongs the period of sensitivity of layers V–VI. Endogenous neurotrophins have also been visual cortex cells to MD [13,54] and produces a further shown to regulate cortical dendritic growth, as demon- loss of visual acuity and shrinkage of cells in the LGN strated by application of Trk receptor bodies (Trk-IgGs) [13]. These results have been interpreted to show that NGF which down-regulate these substances. Downregulation of promotes synaptic consolidation in afferents which are endogenous BDNF disrupts growth of dendritic arbors of driven by visual stimulation when they are competing with neurons in lamina IV while downregulation of endogenous those which are deprived by MD.

NT-3 disrupts dendritic arbor growth of neurons in lamina More recently, the neurotrophins BDNF, NT-3, and VI [105]. The two neurotrophins also have antagonistic NT-4 / 5, have also been shown to influence the formation actions, in that NT-3 can reduce dendritic growth produced of ocular dominance. Thus, in ferret visual cortex local by BDNF in layer IV and BDNF can inhibit dendritic application of BDNF or NT-4 / 5 delays the segregation of growth in layer VI that is produced by NT-3 [105]. The ipsilateral and contralateral geniculocortical afferents that two neurotrophins acting together thus provide a mecha- result in eye-specific ocular dominance columns [26]. nism by which dendritic growth can be stimulated or BDNF also blocks the shift in ocular dominance that

inhibited. occurs in kitten visual cortex neurons after MD [64].

The neurotrophins also mediate growth of axons during Interestingly, reduction of BDNF and NT-4 / 5 in ferret development of the retinotectal pathway. Thus, BDNF and visual cortex by application of Trk-B fusion proteins also NT-3,NT-4 / 5 promote axon arbor growth in chick re- delays segregation of inputs from the two eyes. This result tinotectal co-cultures [83]; and BDNF promotes retinal suggests that either up or down-regulation of neurotrophins ganglion cell axon branching while BDNF antibodies reduces the ability of the fibers to compete for postsynaptic block this branching in frog optic tectum in vivo [37]. space [28].

Recently, BDNF has been shown to interact with NO in Over-expression of BDNF in transgenic mice has a controlling retinal axon growth in chick [59]. Application somewhat different effect. Excess BDNF expressed in the of BDNF in culture, but not NGF or NT-3, protects retinal visual cortex of these mice does not block ocular domi-growth cones and their axons from the collapse and nance plasticity since similar shifts in OD occur in both retraction produced by application of NO. Simultaneous transgenic and wild type mice in response to MD. How-application of both BDNF and NO ‘stabilizes’ these ever, BDNF overexpression does shift the critical period growth cones and axons, possibly related to the appearance for this plasticity to an earlier age [72]. In contrast to these of cytochalasin D-resistant actin filaments that occurs results, Hata et al. [74] have found that infusion of shortly after exposure. Nitric oxide stimulated ADP- exogenous BDNF into visual cortex in kittens desegregates ribosylation of actin has been demonstrated by others [34]. OD columns in both normal and MD kittens, suggesting Finally, individual growth cones are protected from the that an oversupply of this trophic factor promotes exuber-effects of NO when in contact with BDNF coated-latex ant growth of both active and deprived afferents [74]. beads [59]. This study is particularly instructive because it Accelerated expression of BDNF in transgenic mice also

(13)

promotes an earlier termination of the critical period and facilitated by presynaptic depolarization at the neuro-precocious development of visual acuity [80]. muscular synapse. BDNF and presynaptic depolarization NT-4, but not BDNF, NT-3, and NGF, also affects the interact because application of one or the other alone does ferret LGN. Thus, focal application of fluorescent latex not produce the effect. This evidence is an important link beads coated with the TrkB ligand NT-4 blocks atrophy of between synaptic activity and the neurotrophins because it LGN cells in layers connected to the deprived eye demonstrates at the synaptic level that BDNF can selec-[125,126]. This selective effect of NT-4 is surprising given tively strengthen synapses with high levels of impulse the other neurotrophins affect ocular dominance plasticity activity [19].

in the visual cortex of ferret [26,28], rat [101], and kitten [64,74]. In summary, the influences of neurotrophins on

visual cortical plasticity are complex and considerably 7. Conclusions and summary

more data is needed, particularly evidence of how the

neurotrophins alter impulse activity within the axonal Accumulating evidence points to nitric oxide as a arbors which they influence. mediator of activity-dependent refinement of subcortical Recently, several investigators have examined the role visual pathways, including those to the superior colliculus of neurotrophins in the induction of LTP and LTD in and to the lateral geniculate nucleus. In order to properly visual cortex. Application of BDNF in neonatal slices of demonstrate that NO serves as a retrograde message in the rat visual cortex enhances field potentials and EPSCs at refinement of these pathways, the following conditions high concentrations and increases the magnitude of LTP at should be met. (1) NO should be expressed and released in low concentrations, an action that can be blocked by retinorecipient neurons during the time at which the TrkB-IgG fusion proteins or BDNF scavengers. NGF and pathways are being refined. (2) disrupting NO should NT-3 have no effect [1,2]. Others have shown that visual disrupt pathway refinement, preferably by demonstrating cortical LTP is potentiated by BDNF only in response to a that downregulation delays refinement while up-regulation weak tetenus but not to strong theta-burst stimulation [82]. enhances refinement. (3) NO expression should be altered Thus, BDNF enhances synaptic strengthening only under by impulse activity, for example by showing that enuclea-some stimulus conditions and at enuclea-some ages. tion or monocular deprivation reduces the levels of NO or TrkB also helps regulate LTP. When slices of rat visual its synthetic enzyme NOS; (4) NO should differentially cortex are incubated in TrkB IgG receptor, thereby block- affect synapses which are active vs. those which are ing TrkB activation by endogenous ligands, LTP mainte- inactive by promoting stabilization in one and / or retraction nance is impaired, providing further evidence that BDNF in the other.

and its associated Trk receptor are necessary for the The first three conditions have been met in at least some expression of LTP [138]. This group has also shown that model systems. We have cited evidence showing that NO is NGF can regulate LTP. Like BDNF, exogenous application expressed in retinorecipient neurons in the LGN and SC of of NGF to rat visual cortex blocks the maintenance phase some species, and that it’s peak expression in these of LTP, while blockade of endogneous NGF by application neurons occurs during the developmental period in which of TrkA-IgG or of TrkA receptors by use of a monoclonal refinement occurs. Disruption of NO disrupts refinement in antibody, rescues LTP [120]. some retinal pathways, either in e,nNOS knockout mice or BDNF also alters LTD. Exogenous application of BDNF after inhibition of NOS. NO is also down-regulated by reduces the occurrence of LTD in response to a low manipulations that reduce impulse activity in retinal fibers, frequency tetanus in rat visual cortex [82]; and LTD such as MD, providing evidence that impulse activity evoked in layer II / III visual cortical neurons is also mediates NO release. Finally, NO mediated pathway blocked by application of exogenous BDNF [88]. By refinement has been shown to be disrupted by blocking contrast, LTD is enhanced after application of BDNF presynaptic impulse activity, thereby suggesting that the antibodies or BDNF receptor inhibitors [88]. Thus, endog- refinement is activity dependent. Even though there is enous BDNF appears to prevent LTD that is normally accumulating evidence that NO mediates some forms of induced by low frequency stimulation. Additional experi- refinement, we have very little information regarding the ments have shown that the action of BDNF is likely mechanism(s) by which NO alters synapses. Thus, there is

presynaptic [93]. limited data showing that NO can modulate excitatory

In summary, a pattern of evidence is emerging which presynaptic activity in the developing visual system, and implicates BDNF and NT-4 as promoters of synaptic none showing directly the alterations which occur in the strengthening and stabilization. Recently, Poo and col- presynaptic terminal.

leagues [19,154,155] have shown directly at the synaptic One of the conundrums of the NO hypothesis is that NO level that the neurotrophins can potentiate synaptic efficacy must produce a different effect on axons that are appro-in another system. Thus, developappro-ing synapses at the priately targeted vs. those that are inappropriately targeted. neuromuscular junction are potentiated by postsynaptic The Gally et al. [63] hypothesis predicts that the level or release of NT-4 [154,155] and BDNF [19]. This effect is pattern of impulse activity is the signal which determines

(14)

sion in the visual cortex of the rat in vitro, J. Neurophysiol. 76 whether NO will stabilize or eliminate synapses. However,

(1996) 984–994. virtually all of the data published to date which support

[7] T. Battistin, E. Cherubini, Developmental shift from long-term NO as factor in pathway refinement can be explained by _{depression to long-term potentiation at the mossy fibre synapses in} assuming that NO promotes retraction of inappropriately the rat hippocampus, Eur. J. Neurosci. 6 (1994) 1750–1755. targeted axons that are inactive or whose activity is [8] M.F. Bear, A synaptic basis for memory storage in the cerebral

cortex, Proc. Natl. Acad. Sci. USA 93 (1996) 13453–13459. uncorrelated with that of the postsynaptic neuron. There is

[9] M.F. Bear, R.C. Malenka, Synaptic plasticity: LTP and LTD, Curr. as yet no compelling data showing that NO also stabilizes

Opin. Neurobiol. 4 (1994) 389–399.

appropriately targeted axons, and the study of Ernst et al. _{[10] M.F. Bear, L.N. Cooper, F.F. Ebner, A physiological basis for a} [59] shows how stabilization could be achieved by the _{theory of synapse modification, Science 237 (1987) 42–48.} interaction of a neurotrophin promoting axon extension [11] M.F. Bear, W.A. Press, B.W. Connors, Long-term potentiation in

slices of kitten visual cortex and the effects of NMDA receptor and NO promoting retraction. Future experimentation will

blockade, J. Neurophysiol. 67 (1992) 841–851. hopefully clarify the mechanism of action of NO upon

[12] N. Berardi, L. Domenici, L. Parisi, T. Pizzorusso, A. Cellerino, L. presynaptic terminals, and focus upon the second

messen-Maffei, Monocular deprivation effects in the rat visual cortex and gers and signal transduction pathways involved, particu- _{lateral geniculate nucleus are prevented by nerve growth factor} larly the presynaptic signaling cascades that increase or (NGF). I. Visual cortex, Proc. R. Soc. London Ser. B 251 (1993)

17–23. decrease neurotransmitter release or otherwise modify the

[13] N. Berardi, A. Cellerino, L. Domenici, M. Fagiolini, T. Pizzorusso, presynaptic terminal.

A. Cattaneo, L. Maffei, Monoclonal antibodies to nerve growth factor affect the postnatal development of the visual system, Proc. Natl. Acad. Sci. USA 91 (1994) 684–688.

[14] E.L. Bienenstock, L.N. Cooper, P.W. Munro, Theory for the

develop-Acknowledgements

ment of neuron selectivity: orientation specificity and binocular interaction in visual cortex, J. Neurosci. 2 (1982) 32–48. We thank Drs. Hope H. Wu and R. John Cork for their _{[15] B.S. Blais, H.Z. Shouval, L.N. Cooper, The role of presynaptic} significant contributions to studies on pathway refinement activity in monocular deprivation: comparison of homosynaptic and in transgenic mice which we cite in this review. Drs. Paul heterosynaptic mechanisms, Proc. Natl. Acad. Sci. USA 96 (1999)

1083–1087. Huang and Mark Fischman of Massachusetts General

[16] G.A. Bohme, C. Bon, J.M. Stutzmann, A. Doble, J.C. Blanchard, Hospital provided the e,nNOS knockout mouse model. Dr.

Possible involvement of nitric oxide in long-term potentiation, Eur. H.S. Shin of Pohang University, Republic of Korea, _{J. Pharmacol. 199 (1993) 9191–9194.}

provided the Ca channel knockout mouse model. We [17] T. Bonhoeffer, Neurotrophins and activity-dependent development also thank Brett Wilson and Sandie Blanchard for technical of the neocortex, Curr. Opin. Neurobiol. 6 (1996) 119–126.

[18] M. Bothwell, Functional interactions of neurotrophins and neuro-assistance. A large number of undergraduate students

trophin receptors, Annu. Rev. Neurosci. 18 (1995) 223–253. supported by the Howard Hughes Foundation and the

[19] L. Boulanger, M.M. Poo, Presynaptic depolarization facilitates Summer Undergraduate in Neuroscience (SUN) program _{neurotrophin-induced synaptic potentiation, Nature Neurosci. 2} of LSU Health Sciences Center collected some of the data. (1999) 346–351.

Our research was supported by USPHS grant NS-36000 [20] Y. Bozzi, T. Pizzorusso, F. Cremisi, F.M. Rossi, G. Barasacchi, L. Maffei, Monocular deprivation decreases the expression of mes-from the National Institute of Neurological Disorders and

senger RNA for brain-derived neurotrophic factor in the rat visual Stroke and grant EY-02973 from the National Eye

Insti-cortex, Neuroscience 69 (1995) 1133–1144.

tute. _{[21] D.S. Bredt, S.H. Snyder, Nitric oxide mediates glutamate-linked} enhancement of cGMP levels in the cerebellum, Proc. Natl Acad. Sci. USA 86 (1989) 9030–9033.

[22] D.S. Bredt, S.H. Snyder, Isolation of nitric oxide synthase, a

References _{calmodulin-requiring enzyme, Proc. Natl Acad. Sci. USA 87 (1990)}

682–685.

[1] Y. Akaneya, T. Tsumoto, H. Hatanaka, Brain-derived neurotropic [23] D.S. Bredt, P.M. Hwang, S.H. Snyder, Localization of nitric oxide factor blocks long-term depression in rat visual cortex, J. Neuro- synthase indicating a neural role for nitric oxide, Nature 347 (1990)

physiol. 76 (1996) 4198–4201. 768–770.

[2] Y. Akaneya, T. Tsumoto, T. Kinoshita, H. Hatanaka, Brain-derived [24] D.S. Bredt, C.E. Glatt, P.M. Hwang, M. Fotuhi, T.M. Dawson, S.H. neurotrophic factor enhances long-term potentiation in rat visual Snyder, Nitric oxide synthase protein and mRNA are discretely cortex, J. Neurosci. 17 (1997) 6707–6716. localized in neuronal populations of the mammalian CNS together [3] O. Arancio, V. Lev-Ram, R.Y. Tsien, E.R. Kandel, R.D. Hawkins, with NADPH diaphorase, Neuron 7 (1991) 615–624.

Nitric Oxide acts as a retrograde messenger during long-term [25] S.G. Brickley, E.A. Dawes, M.J. Keating, S. Grant, Synchronizing potentiation in cultured hippocampal neurons, J. Physiol. Paris 90 retinal activity in both eyes disrupts binocular map development in (1996) 321–322. the optic tectum, J. Neurosci. 18 (1998) 1491–1504.

[4] A. Artola, W. Singer, Long-term depression of excitatory synaptic [26] R.J. Cabelli, A. Hohn, C.J. Shatz, Inhibition of ocular dominance transmission and its relationship to long-term potentiation, Trends column formation by infusion of NT-4 / 5 or BDNF, Science 267

Neurosci. 16 (1993) 480–487. (1995) 1662–1666.

[5] A. Artola, S. Brocher, W. Singer, Different voltage-dependent [27] R.J. Cabelli, K.L. Allendoerfer, M.J. Radeke, A.A. Welcher, S.C. thresholds for long-term depression and long-term potentiation in Feinstein, C.J. Shatz, Changing patterns of expression and subcellu-slices of rat visual cortex, Nature 347 (1990) 69–72. lar localization of TrkB in the developing visual system, J. Neurosci. [6] A. Artola, T. Hensch, W. Singer, Calcium-induced long-term depres- 16 (1996) 7965–7980.

(1)

promotes an earlier termination of the critical period and

facilitated by presynaptic depolarization at the

neuro-precocious development of visual acuity [80].

muscular synapse. BDNF and presynaptic depolarization

NT-4, but not BDNF, NT-3, and NGF, also affects the

interact because application of one or the other alone does

ferret LGN. Thus, focal application of fluorescent latex

not produce the effect. This evidence is an important link

beads coated with the TrkB ligand NT-4 blocks atrophy of

between synaptic activity and the neurotrophins because it

LGN cells in layers connected to the deprived eye

demonstrates at the synaptic level that BDNF can

selec-[125,126]. This selective effect of NT-4 is surprising given

tively strengthen synapses with high levels of impulse

the other neurotrophins affect ocular dominance plasticity

activity [19].

in the visual cortex of ferret [26,28], rat [101], and kitten

[64,74]. In summary, the influences of neurotrophins on

visual cortical plasticity are complex and considerably

7. Conclusions and summary

more data is needed, particularly evidence of how the

neurotrophins alter impulse activity within the axonal

Accumulating evidence points to nitric oxide as a

arbors which they influence.

mediator of activity-dependent refinement of subcortical

Recently, several investigators have examined the role

visual pathways, including those to the superior colliculus

of neurotrophins in the induction of LTP and LTD in

and to the lateral geniculate nucleus. In order to properly

visual cortex. Application of BDNF in neonatal slices of

demonstrate that NO serves as a retrograde message in the

rat visual cortex enhances field potentials and EPSCs at

refinement of these pathways, the following conditions

high concentrations and increases the magnitude of LTP at

should be met. (1) NO should be expressed and released in

low concentrations, an action that can be blocked by

retinorecipient neurons during the time at which the

TrkB-IgG fusion proteins or BDNF scavengers. NGF and

pathways are being refined. (2) disrupting NO should

NT-3 have no effect [1,2]. Others have shown that visual

disrupt pathway refinement, preferably by demonstrating

cortical LTP is potentiated by BDNF only in response to a

that downregulation delays refinement while up-regulation

weak tetenus but not to strong theta-burst stimulation [82].

enhances refinement. (3) NO expression should be altered

Thus, BDNF enhances synaptic strengthening only under

by impulse activity, for example by showing that

enuclea-some stimulus conditions and at enuclea-some ages.

tion or monocular deprivation reduces the levels of NO or

TrkB also helps regulate LTP. When slices of rat visual

its synthetic enzyme NOS; (4) NO should differentially

cortex are incubated in TrkB IgG receptor, thereby block-

affect synapses which are active vs. those which are

ing TrkB activation by endogenous ligands, LTP mainte-

inactive by promoting stabilization in one and / or retraction

nance is impaired, providing further evidence that BDNF

in the other.

and its associated Trk receptor are necessary for the

The first three conditions have been met in at least some

expression of LTP [138]. This group has also shown that

model systems. We have cited evidence showing that NO is

NGF can regulate LTP. Like BDNF, exogenous application

expressed in retinorecipient neurons in the LGN and SC of

of NGF to rat visual cortex blocks the maintenance phase

some species, and that it’s peak expression in these

of LTP, while blockade of endogneous NGF by application

neurons occurs during the developmental period in which

of TrkA-IgG or of TrkA receptors by use of a monoclonal

refinement occurs. Disruption of NO disrupts refinement in

antibody, rescues LTP [120].

some retinal pathways, either in e,nNOS knockout mice or

BDNF also alters LTD. Exogenous application of BDNF

after inhibition of NOS. NO is also down-regulated by

reduces the occurrence of LTD in response to a low

manipulations that reduce impulse activity in retinal fibers,

frequency tetanus in rat visual cortex [82]; and LTD

such as MD, providing evidence that impulse activity

evoked in layer II / III visual cortical neurons is also

mediates NO release. Finally, NO mediated pathway

blocked by application of exogenous BDNF [88]. By

refinement has been shown to be disrupted by blocking

contrast, LTD is enhanced after application of BDNF

presynaptic impulse activity, thereby suggesting that the

antibodies or BDNF receptor inhibitors [88]. Thus, endog-

refinement is activity dependent. Even though there is

enous BDNF appears to prevent LTD that is normally

accumulating evidence that NO mediates some forms of

induced by low frequency stimulation. Additional experi-

refinement, we have very little information regarding the

ments have shown that the action of BDNF is likely

mechanism(s) by which NO alters synapses. Thus, there is

presynaptic [93].

limited data showing that NO can modulate excitatory

In summary, a pattern of evidence is emerging which

presynaptic activity in the developing visual system, and

implicates BDNF and NT-4 as promoters of synaptic

none showing directly the alterations which occur in the

strengthening and stabilization. Recently, Poo and col-

presynaptic terminal.

leagues [19,154,155] have shown directly at the synaptic

One of the conundrums of the NO hypothesis is that NO

level that the neurotrophins can potentiate synaptic efficacy

must produce a different effect on axons that are

appro-in another system. Thus, developappro-ing synapses at the

priately targeted vs. those that are inappropriately targeted.

neuromuscular junction are potentiated by postsynaptic

The Gally et al. [63] hypothesis predicts that the level or

release of NT-4 [154,155] and BDNF [19]. This effect is

pattern of impulse activity is the signal which determines

(2)

sion in the visual cortex of the rat in vitro, J. Neurophysiol. 76

whether NO will stabilize or eliminate synapses. However,

(1996) 984–994.

virtually all of the data published to date which support

[7] T. Battistin, E. Cherubini, Developmental shift from long-term

NO as factor in pathway refinement can be explained by

_{depression to long-term potentiation at the mossy fibre synapses in}

assuming that NO promotes retraction of inappropriately

the rat hippocampus, Eur. J. Neurosci. 6 (1994) 1750–1755.

targeted axons that are inactive or whose activity is

[8] M.F. Bear, A synaptic basis for memory storage in the cerebral cortex, Proc. Natl. Acad. Sci. USA 93 (1996) 13453–13459.

uncorrelated with that of the postsynaptic neuron. There is

[9] M.F. Bear, R.C. Malenka, Synaptic plasticity: LTP and LTD, Curr.

as yet no compelling data showing that NO also stabilizes

Opin. Neurobiol. 4 (1994) 389–399.

appropriately targeted axons, and the study of Ernst et al.

_{[10] M.F. Bear, L.N. Cooper, F.F. Ebner, A physiological basis for a}

[59] shows how stabilization could be achieved by the

_{theory of synapse modification, Science 237 (1987) 42–48.}

interaction of a neurotrophin promoting axon extension

[11] M.F. Bear, W.A. Press, B.W. Connors, Long-term potentiation in

slices of kitten visual cortex and the effects of NMDA receptor

and NO promoting retraction. Future experimentation will

blockade, J. Neurophysiol. 67 (1992) 841–851.

hopefully clarify the mechanism of action of NO upon

[12] N. Berardi, L. Domenici, L. Parisi, T. Pizzorusso, A. Cellerino, L.

presynaptic terminals, and focus upon the second

messen-Maffei, Monocular deprivation effects in the rat visual cortex and

gers and signal transduction pathways involved, particu-

_{lateral geniculate nucleus are prevented by nerve growth factor}

larly the presynaptic signaling cascades that increase or

(NGF). I. Visual cortex, Proc. R. Soc. London Ser. B 251 (1993)

17–23.

decrease neurotransmitter release or otherwise modify the

[13] N. Berardi, A. Cellerino, L. Domenici, M. Fagiolini, T. Pizzorusso,

presynaptic terminal.

A. Cattaneo, L. Maffei, Monoclonal antibodies to nerve growth factor affect the postnatal development of the visual system, Proc. Natl. Acad. Sci. USA 91 (1994) 684–688.

[14] E.L. Bienenstock, L.N. Cooper, P.W. Munro, Theory for the

develop-Acknowledgements

ment of neuron selectivity: orientation specificity and binocular interaction in visual cortex, J. Neurosci. 2 (1982) 32–48.

We thank Drs. Hope H. Wu and R. John Cork for their

_{[15] B.S. Blais, H.Z. Shouval, L.N. Cooper, The role of presynaptic}

significant contributions to studies on pathway refinement

activity in monocular deprivation: comparison of homosynaptic and

in transgenic mice which we cite in this review. Drs. Paul

heterosynaptic mechanisms, Proc. Natl. Acad. Sci. USA 96 (1999) 1083–1087.

Huang and Mark Fischman of Massachusetts General

[16] G.A. Bohme, C. Bon, J.M. Stutzmann, A. Doble, J.C. Blanchard,

Hospital provided the e,nNOS knockout mouse model. Dr.

Possible involvement of nitric oxide in long-term potentiation, Eur.

H.S. Shin of Pohang University, Republic of Korea,

_{J. Pharmacol. 199 (1993) 9191–9194.}

provided the Ca

channel knockout mouse model. We

[17] T. Bonhoeffer, Neurotrophins and activity-dependent development

also thank Brett Wilson and Sandie Blanchard for technical

of the neocortex, Curr. Opin. Neurobiol. 6 (1996) 119–126. [18] M. Bothwell, Functional interactions of neurotrophins and

neuro-assistance. A large number of undergraduate students

trophin receptors, Annu. Rev. Neurosci. 18 (1995) 223–253.

supported by the Howard Hughes Foundation and the

[19] L. Boulanger, M.M. Poo, Presynaptic depolarization facilitates

Summer Undergraduate in Neuroscience (SUN) program

_{neurotrophin-induced synaptic potentiation, Nature Neurosci. 2}

of LSU Health Sciences Center collected some of the data.

(1999) 346–351.

Our research was supported by USPHS grant NS-36000

[20] Y. Bozzi, T. Pizzorusso, F. Cremisi, F.M. Rossi, G. Barasacchi, L. Maffei, Monocular deprivation decreases the expression of

mes-from the National Institute of Neurological Disorders and

senger RNA for brain-derived neurotrophic factor in the rat visual

Stroke and grant EY-02973 from the National Eye

Insti-cortex, Neuroscience 69 (1995) 1133–1144.

tute.

_{[21] D.S. Bredt, S.H. Snyder, Nitric oxide mediates glutamate-linked}

enhancement of cGMP levels in the cerebellum, Proc. Natl Acad. Sci. USA 86 (1989) 9030–9033.

[22] D.S. Bredt, S.H. Snyder, Isolation of nitric oxide synthase, a

References

_{calmodulin-requiring enzyme, Proc. Natl Acad. Sci. USA 87 (1990)}

682–685.

physiol. 76 (1996) 4198–4201. 768–770.

Neurosci. 16 (1993) 480–487. (1995) 1662–1666.

(3)

[28] R.J. Cabelli, D.L. Shelton, R.A. Segal, C.J. Shatz, Blockade of senger molecule in brain: The free radical, nitric oxide, Ann. Neurol. endogenous ligands of TrkB inhibits formation of ocular dominance 32 (1992) 297–311.

columns, Neuron 19 (1997) 63–76. [51] T.M. Dawson, M. Sasaki, M. Gonzalez-Zuluet, V.L. Dawson, [29] P. Calabresi, P. Gubellini, D. Centonze, G. Scancesario, M. Morello, Regulation of neuronal nitric oxide synthase and identification of M. Giogri, A. Pisani, G. Bernardi, A critical role of the nitric novel nitric oxide signaling pathways, Prog. Brain Res. 118 (1998) oxide / cGMP pathway in corticostriatal long-term depression, J. 1–11.

Neurosci. 19 (1999) 2489–2499. [52] L. Domenici, N. Berardi, G. Carmignoto, G. Vantini, L. Maffei, [30] G. Carmignoto, R. Canella, P. Candeo, M.C. Comelli, L. Maffei, Nerve growth factor prevents the amblyopic effects of monocular

Effects of nerve growth factor on neuronal plasticity of the kitten deprivation, Proc. Natl. Acad. Sci. USA 88 (1991) 8811–8815. visual cortex, J. Physiol. 464 (1993) 343–360. [53] L. Domenici, A. Cellerino, L. Maffei, Monocular deprivation effects [31] E. Castren, F. Zafra, H. Thoenen, D. Lindholm, Light regulates in the rat visual cortex and lateral geniculate nucleus are prevented expression of brain-deprived neurotrophic factor mRNA in rat visual by nerve growth factor (NGF) II. Lateral geniculate nucleus, Proc. cortex, Proc. Natl. Acad. Sci. USA 89 (1992) 9444–9448. R. Soc. London Ser. B 251 (1993) 25–31.

[32] B. Chapman, M.D. Jacobson, H.O. Reiter, M.P. Stryker, Ocular [54] L. Domenici, A. Cellerino, N. Berardi, A. Cattaneo, L. Maffei, dominance shift in kitten visual cortex caused by imbalance in Antibodies to nerve growth factor (NGF) prolong the sensitive retinal electrical activity, Nature 324 (1986) 154–156. period for monocular deprivation in the rat, Neuroreport 5 (1994)

2041–2044. [33] S. Choi, D.M. Lovinger, Decreased probability of neurotransmitter

release underlies striatal long-term depression and postnatal de- [55] M.R. Domenici, N. Berretta, E. Cherubini, Two distinct forms of velopment of corticostriatal synapses, Proc. Natl. Acad. Sci. USA 94 long-term depression coexist at the mossy fiber-CA3 synapse in the (1997) 2665–2670. hippocampus during development, Proc. Natl. Acad. Sci. USA 95

(1998) 8310–8315. [34] R. Clancy, J. Leszczynska, A. Armin, D. Levartovsky, S.B.

Abram-son, Nitric oxide stimulates ADP ribosylation of actin in association [56] S.M. Dudek, M.J. Friedlander, Developmental down-regulation of with the inhibition of actin polymerization in human neutrophils, J. LTD in cortical layer IV and its independence of modulation by Leukocyte Biol. 58 (1995) 196–202. inhibition, Neuron 16 (1996) 1097–1106.

[35] H.T. Cline, M. Constantine-Paton, NMDA receptor antagonists [57] D.M. Egelman, R.D. King, P.R. Montague, Interaction of nitric disrupt the retinotectal topographic map, Neuron 3 (1998) 413–426. oxide and external calcium fluctuations: a possible substrate for rapid information retrieval, Prog. Brain Res. 118 (1998) 199–211. [36] H.T. Cline, E.A. Debski, M. Constantine-Paton, NMDA receptor

antagonist desegregates eye-specific stripes, Proc. Natl Acad. Sci. [58] F. Ernst, H.H. Wu, E.E. El-Fakahany, S.C. McLoon, NMDA USA 84 (1987) 4342–4345. receptor mediated refinement of a transient retinotectal projection [37] S. Cohen-Cory, S.E. Fraser, Effects of brain-derived neurotrophic requires nitric oxide, J. Neurosci. 19 (1999) 229–235.

factor on optic axon branching and remodelling in vivo, Nature 378 [59] A.F. Ernst, G. Gallo, P.C. Letourneau, S.C. McLoon, Stabilization of (1995) 192–196. growing retinal axons by the combined signaling of nitric oxide and [38] R.J. Colello, R.W. Guillery, The early development of retinal brain-derived neurotrophic factor, J. Neurosci. 20 (2000) 1458–

ganglion cells with uncrossed axons in the mouse: Retinal position 1469.

and axonal course, Development 108 (1990) 513–523. [60] D.E. Feldman, R.A. Nicoll, R.C. Malenka, J.T.R. Isaac, Long-term [39] M. Constantine-Paton, H.T. Cline, LTP and activity-dependent depression at thalamocortical synapses in developing rat

somato-synaptogenesis: the more alike they are, the more different they sensory cortex, Neuron 21 (1998) 347–357.

become, Curr. Opin. Neurobiol. 8 (1998) 139–148. [61] E.M. Finney, C.J. Shatz, Establishment of patterned thalamocortical [40] R.J. Cork, T. Calhoun, M. Perrone, R.R. Mize, Postnatal develop- connections does not require nitric oxide synthase, J. Neurosci. 18

ment of nitric oxide synthase expression in the mouse superior (1998) 8826–8838.

colliculus, J. Comp. Neurol. (2000) in press. [62] L. Galli, L. Maffei, Spontaneous impulse activity of rat retinal [41] R.J. Cork, M.Y. Jenkins, H.-S. Shin, R.R. Mize, Delayed refinement ganglion cells in prenatal life, Science 242 (1998) 90–91.

of the visual pathway in mice with a targeted disruption of the [63] J.A. Gally, P.R. Montague, G.N. Reeke Jr., G.M. Edelman, The NO calcium channelb3-subunit gene, Neurosci. Abs. 26 (2000) in press. hypothesis: Possible effects of a short-lived, rapidly diffusable [42] W.M. Cowan, J.W. Fawcett, D.D.M. O’Leary, B.B. Stanfield, signal in the development and function of the nervous system, Proc.

Regressive events in neurogenesis, Science 225 (1984) 1258–1265. Natl. Acad. Sci. USA 87 (1990) 3547–3551.

[43] M.C. Crair, R.C. Malenka, A critical period for long-term potentia- [64] R.A. Galuske, D.S. Kim, E. Castren, H. Thoenen, W. Singer, tion at thalamocortical synapses, Nature 375 (1995) 325–328. Brain-derived neurotrophic factor reversed experience-dependent [44] K.S. Cramer, M. Sur, The role of NMDA receptors and nitric oxide synaptic modifications in kitten visual cortex, Eur. J. Neurosci. 8

in retinogeniculate development, Prog. Brain Res. 108 (1996) 235– (1996) 1554–1559.

244. [65] J. Garthwaite, Glutamate, nitric oxide and cell–cell signaling in the [45] K.S. Cramer, M. Sur, Blockade of afferent impulse activity disrupts nervous system, Trends Neurosci. 14 (1991) 60–67.

on / off sublamination in the ferret lateral geniculate nucleus, Dev. [66] J. Garthwaite, S.L. Charles, R. Chess-Williams, Endothelium-de-Brain. Res. 98 (1997) 287–290. rived relaxing factor release on activation of NMDA receptors [46] K.S. Cramer, M. Sur, The neuronal form of nitric oxide synthase is suggests role as intracellular messenger in the brain, Nature 336

required for pattern formation by retinal afferents in the ferret lateral (1988) 385–388.

geniculate nucleus, Dev. Brain Res. 116 (1999) 79–86. [67] S.M. Gibbs, J.W. Truman, Nitric oxide and cyclic GMP regulate [47] K.S. Cramer, A. Angelucci, J.O. Hahm, M.B. Bogdanov, M. Sur, A retinal patterning in the optic lobe of Drosophila melanogaster,

role for nitric oxide in the development of the ferret retinogeniculate Neuron 20 (1998) 83–93.

projection, J. Neurosci. 16 (1996) 7995–8004. [68] P. Godement, J. Saluan, M. Imbert, Prenatal and postnatal develop-[48] K.S. Cramer, C.A. Leamey, M. Sur, Nitric oxide as a signaling ment of retinogeniculate and retinocollicular projections in the

molecule in visual system development, Prog. Brain Res. 118 mouse, J. Comp. Neurol. 230 (1984) 552–575.

(1998) 101–114. [69] P. Godement, J. Saluan, C. Metin, Fate of uncrossed retinal [49] F. Crepel, D. Jaillard, Protein kinases, nitric oxide and long-term projections following early or late prenatal monocular enucleation in

depression of synapses in the cerebellum, Neuro. Report 1 (1990) the mouse, J. Comp. Neurol. 255 (1987) 97–109.

133–136. [70] C.S. Goodman, C.J. Shatz, Developmental mechanisms that generate [50] T.M. Dawson, V.L. Dawson, S.H. Snyder, A novel neuronal mes- precise patterns of neuronal connectivity, Cell 72 (1993) 77–98.

(4)

[71] J.-O. Hahm, R.B. Langdon, M. Sur, Disruption of retinogeniculate neurotrophic factor blocks long-term depression in solitary neurones afferent segregation by antagonists to NMDA receptors, Nature 351 cultured from rat-visual cortex, J. Physiol. (Lond.) 524 (2000)

(1991) 568–570. 195–204.

[72] J.L. Hanover, Z.J. Huang, S. Tonegawa, M.P. Stryker, Brain-derived [94] J.R. Lancaster, Simulation of the diffusion and reaction of en-neurotrophic factor overexpression induces precocious critical dogenously produced nitric oxide, Proc. Natl. Acad. Sci. USA 17 period in mouse visual cortex, J. Neurosci (Online) 19 (1999) RC40. (1994) 8137–8141.

[73] K. Harsanyi, M.J. Friedlander, Transient synaptic potentiation in the [95] P.W. Land, R.D. Lund, Development of the rat’s uncrossed retinotec-visual cortex. II. Developmental regulation, J. Neurophysiol. 77 tal pathway and its relation to plasticity studies, Science 205 (1979)

(1997) 1284–1293. 698–700.

[74] Y. Hata, M. Ohshima, S. Ichisaka, M. Wakita, M. Fukuda, T. [96] V. Lev-Ram, L.R. Makings, P.F. Keitz, J.P.Y. Kao, R.Y. Tsien, Tsumoto, Brain-derived neurotrophic factor expands ocular domi- Long-term depression in cerebellar Purkinje neurons results from

nance columns in visual cortex in monocularly deprived and coincidence of nitric oxide and depolarization-induced Ca trans-nondeprived kittens but does not in adult cats, J. Neurosci. (Online) ients, Neuron 15 (1995) 407–415.

20 (2000) RC57. [97] V. Lev-Ram, T. Jiang, J. Wood, D.S. Lawrence, R.Y. Tsien, [75] R.D. Hawkins, H. Son, O. Arancio, Nitric oxide as a retrograde Synergies and coincidence requirements between NO, cGMP, and

messenger during long-term potentiation in hippocampus, Prog. Ca in the induction of cerebellar long-term depression, Neuron 18

Brain Res. 118 (1998) 155–172. (1997) 1025–1038.

[76] D.T. Hess, S.I. Patterson, D.S. Smith, J.H.P. Skene, Neuronal growth [98] V. Lev-Ram, Z. Nebyelul, M.H. Ellisman, P.L. Huang, R.Y. Tsien, cone collapse and inhibition of protein fatty acylation by nitric Absence of cerebellar long-term depression in mice lacking neuronal oxide, Nature 366 (1993) 562–565. nitric oxide synthase, Learn. Mem. 4 (1997) 169–177.

[77] S. Hindley, B.H.J. Juurlink, J.W. Gysbers, P.J. Middlemiss, M.A.R. [99] F.-S. Lo, R.R. Mize, Synaptic regulation of L-type Ca21channel Herman, M.P. Rathbone, Nitric oxide donors enhance neurotrophin- activity and long-term depression during refinement of the re-induced neurite outgrowth through a cGMP-dependent mechanism, tinocollicular pathway in developing rodent superior colliculus, J. J. Neurosci. Res. 47 (1997) 427–439. Neurosci. 20 (RC58) (2000) 1–6.

[78] C.E. Holt, W.A. Harris, Target selection: invasion, mapping and cell [100] F.-S. Lo, R.R. Mize, NMDA receptor-independent long-term choice, Curr. Opin. Neurobiol. 8 (1998) 98–105. depression occurs during refinement of the retinocollicular pathway

in developing rodent superior colliculus, (2000) in preparation. [79] P.L. Huang, E.H. Lo, Genetic analysis of NOS isoforms using nNOS

and eNOS knockout animals, Prog. Brain Res. 118 (1998) 13–25. [101] L. Maffei, N. Berardi, L. Domenici, V. Parisi, T. Pizzorusso, Nerve [80] Z.J. Huang, A. Kirkwood, T. Pizzorusso, V. Porciatti, B. Morales, growth factor (NGF) prevents the shift in ocular dominance M.F. Bear, L. Maffei, S. Tonegawa, BDNF regulates the maturation distribution of visual cortical neurons in monocularly deprived rats, of inhibition and the critical period of plasticity in mouse visual J. Neurosci. 12 (1992) 4651–4662.

cortex, Cell 98 (1999) 739–755. [102] R.C. Malenka, R.A. Nicoll, NMDA-receptor-dependent synaptic [81] D.H. Hubel, T.N. Wiesel, Ferrier lecture. Functional architecture of plasticity: multiple forms and mechanism, Trends Neurosci. 16

macaque monkey visual cortex, Proc. R. Soc. Lond. B. Biol. Sci. (1993) 521–527.

198 (1977) 1–59. [103] R.C. Malenka, R.A. Nicoll, Long-term potentiation — a decade of [82] K.M. Huber, N.B. Sawtell, M.F. Bear, Brain-derived neurotrophic progress?, Science 285 (1999) 1870–1874.

factor alters the synaptic modification threshold in visual cortex, [104] A.K. McAllister, D.C. Lo, L.C. Katz, Neurotrophins regulate Neuropharmacology 37 (1998) 571–579. dendritic growth in developing visual cortex, Neuron 15 (1995) [83] A. Inoue, J.R. Sanes, Lamina-specific connectivity in the brain: 791–803.

regulation by N-cadherin, neurotrophins, and glycoconjugates, Sci- [105] A.K. McAllister, L.C. Katz, D.C. Lo, Opposing roles for endogen-ence 276 (1997) 1428–1431. ous BDNF and NT-3 in regulating cortical dendritic growth, [84] Y. Izumi, D.B. Clifford, C.F. Zorumski, Inhibition of long-term Neuron 18 (1997) 767–778.

potentiation by NMDA-mediated nitric oxide release, Science 257 [106] A.K. McAllister, L.C. Katz, D.C. Lo, Neurotrophins and synaptic (1992) 1273–1276. plasticity, Ann. Rev. Neurosci. 22 (1999) 295–318.

[85] N. Kato, A. Artola, W. Singer, Developmental changes in the [107] M.K. Meffert, B.A. Premack, H. Schulman, Nitric oxide stimulates susceptibility to long-term potentiation of neurons in rat visual Ca(21)-independent synaptic vesicle release, Neuron 12 (1994) cortex slices, Dev. Brain Res. 60 (1991) 43–50. 1235–1244.

[86] L.C. Katz, C.J. Shatz, Synaptic activity and the construction of [108] M.K. Meffert, N.C. Calakos, R.H. Scheller, H. Schulman, Nitric cortical circuits, Science 274 (1996) 1133–1138. oxide modulates synaptic vesicle docking fusion reactions, Neuron [87] F. Kimura, A. Nishigori, T. Shirokawa, T. Tsumoto, Long-term 16 (1996) 1229–1236.

potentiation and N-methyl-D-aspartate receptors in the visual cortex [109] M. Meister, R.O. Wong, D.A. Baylor, C.J. Shatz, Synchronous of young rats, J. Physiol. (Lond.) 414 (1989) 125–144. bursts of action potentials in ganglion cells of the developing [88] S. Kinoshita, N. Taniguchi, R. Katoh-Semba, H. Hatanaka, T. mammalian retina, Science 252 (1991) 939–943.

Tsumoto, Brain-derived neurotrophic factor prevents low frequency [110] K.D. Miller, J.B. Keller, M.P. Stryker, Ocular dominance column inputs from inducing long-term depression in the developing visual development: analysis and simulation, Science 245 (1989) 605– cortex, J. Neurosci. 19 (1999) 2122–2130. 615.

[89] A. Kirkwood, M.F. Bear, Hebbian synapses in visual cortex, J. [111] R.R. Mize, F.-S. Lo, The metabotropic glutamate receptor is not Neurosci. 14 (1994) 1634–1645. involved in the induction of LTD in the retinocollicular pathway of [90] A. Kirkwood, M.F. Bear, Homosynaptic long-term depression in the neonatal rats, Neurosci. Abs. 26 (2000) in press.

visual cortex, J. Neurosci. 14 (1994) 3404–3412. [112] R.R. Mize, C.A. Scheiner, M.F. Salvatore, R.J. Cork, Inhibition of [91] A. Kirkwood, H.-K. Lee, M.F. Bear, Co-regulation of long-term nitric oxide synthase fails to disrupt the development of cholinergic potentiation and experience-dependent plasticity in visual cortex by fiber patches in the rat superior colliculus, Dev. Neurosci. 19 age and experience, Nature 375 (1995) 328–331. (1997) 260–273.

[92] A. Kirkwood, A. Silva, M.F. Bear, Age-dependent decrease of [113] R.R. Mize, H.H. Wu, R.J. Cork, C.A. Scheiner, The role of nitric synaptic plasticity in the neocortex of alphaCaMKII mutant mice, oxide in development of the patch-cluster system and retinocollicu-Proc. Natl. Acad. Sci. USA 94 (1997) 3380–3383. lar pathways in the rodent superior colliculus, Prog. Brain Res. 118 [93] E. Kumura, F. Kimura, N. Taniguchi, T. Tsumoto, Brain-derived (1998) 133–154.

(5)

[114] P.R. Montague, J.A. Gally, G.M. Edelman, Spatial signaling in the [133] J.T. Schmidt, M. Buzzard, Activity-driven sharpening of the development and function of neural connections, Cereb. Cortex. 1 regenerating retinotectal projection: effects of blocking or (1991) 199–220. synchronizing activity on the morphology of individual

regenerat-ing arbors, J. Neurobiol. 21 (1990) 900–917. [115] Y. Namkung, S.M. Smith, S.B. Lee, N.V. Skrypnyk, H.-L. Kim, H.

Chin, R.H. Scheller, R.W. Tsien, H.-S. Shin, Targeted disruption of [134] J.T. Schmidt, M. Buzzard, Activity-driven sharpening of the

21 21

the Ca channelb3subunit reduces N- and L-type Ca channel retinotectal projection in goldfish: development under stroboscopic activity in and alters the voltage-dependent activation of P/ Q-type illumination prevents sharpening, J. Neurobiol. 24 (1993) 384– Ca21channels in neurons, Proc. Natl. Acad. Sci. USA 9 (1998) 399.

12010–12015. [135] A.A. Schoups, R.C. Elliott, W.J. Friedman, I.B. Black, NGF and [116] T.J. O’Dell, R.D. Hawkins, E.R. Kandel, O. Arancio, Tests of the BDNF are differentially modulated by visual experience in the roles of two diffusible substances in long-term potentiation: developing geniculocortical pathway, Brain Res. 86 (1995) 326– evidence for nitric oxide as a possible early retrograde messenger, 334.

Proc. Natl Acad. Sci. USA 88 (1991) 11285–11289. [136] E.M. Schuman, D.V. Madison, Nitric oxide and synaptic function, [117] D.D. O’Leary, J.W. Fawcett, W.M. Cowan, Topographic targeting Annu. Rev. Neurosci. 17 (1994) 153–183.

errors in the retinocollicular projection and their elimination by [137] E. Sermasi, D. Tropea, L. Domenici, A new form of synaptic selective ganglion cell death, J. Neurosci. 6 (1986) 3692–3705. plasticity is transiently expressed in the developing rat visual [118] R.W. Oppenheim, The concept of uptake and retrograde transport cortex: a modulatory role for visual experience and brain-derived

of neurotrophic molecules during development: history and present neurotrophic factor, Neuroscience 91 (1999) 163–173.

status, Neurochem. Res. 21 (1996) 769–777. [138] E. Sermasi, E. Margotti, A. Cattaneo, L. Domenici, Trk B [119] A.T. Perkins IV, T.J. Teyler, A critical period for long-term signalling controls LTP but not LTD expression in the developing

potentiation in the developing rat visual cortex, Brain Res. 439 rat visual cortex, Eur. J. Neurosci. 12 (2000) 1411–1419. (1988) 222–229. [139] C.J. Shatz, Impulse activity and the patterning of connections [120] E. Pesavento, E. Margotti, M. Righi, A. Cattaneo, L. Domenici, during CNS development, Neuron 5 (1990) 745–756.

Blocking the NGF-TrkA interaction rescues the developmental loss [140] C.J. Shatz, M.P. Stryker, Prenatal tetrodotoxin infusion blocks of LTP in the rat visual cortex: role of the cholinergic system, segregation of retinogeniculate afferents, Science 242 (1988) 87–

Neuron 25 (2000) 165–175. 89.

[121] T.A. Reh, M. Constantine-Paton, Eye-specific segregation requires [141] D.K. Simon, D.D.M. O’Leary, Development of topographic order neural activity in three-eyed Rana pipiens, J. Neurosci. 5 (1985) in the mammalian retinocollicular projection, J. Neurosci. 12

1132–1143. (1992) 1212–1232.

[122] S.N.M. Reid, N.W. Daw, D. Czepita, H.J. Flavin, W.C. Sessa, [142] D.K. Simon, G.T. Prusky, D.D.M. O’Leary, M. Constantine-Paton, Inhibition of nitric oxide synthase does not alter ocular dominance N-methyl-d-aspartate receptor antagonists disrupt the formation of

shifts in kitten visual cortex, J. Physiol. (Lond) 494 (1996) 511– a mammalian neural map, Proc. Natl. Acad. Sci. USA 89 (1992)

517. 10593–10597.

[123] R.C. Renteria, M. Constantine-Paton, Exogenous nitric oxide [143] D.K. Simon, A.L. Roskies, D.D. O’Leary, Plasticity in the develop-causes collapse of retinal ganglion cell axonal growth cones in ment of topographic order in the mammalian retinocollicular vitro, J. Neurobiol. 29 (1996) 415–428. projection, Dev. Biol. 162 (1994) 384–393.

[124] R.C. Renteria, M. Constantine-Paton, Nitric oxide in the retinotec- [144] W. Singer, Development and plasticity of cortical processing tal system: a signal but not a retrograde messenger during map architectures, Science 270 (1995) 758–764.

refinement and segregation, J. Neurosci. 19 (1999) 7066–7076. [145] W.D. Snider, Functions of the neurotrophins during nervous system [125] D.R. Riddle, D.C. Lo, L.C. Katz, NT-4-mediated rescue of lateral development: what the knockouts are teaching us, J. Neurosci. 14

geniculate neurons from effects of monocular deprivation, Nature (1994) 5187–5201.

378 (1995) 189–191. [146] H. Son, R.D. Hawkins, K. Martin, M. Kiebler, P.L. Huang, M.C. [126] D.R. Riddle, L.C. Katz, D.C. Lo, Focal delivery of neurotrophins Fishman, E.R. Kandel, Long-term potentiation is reduced in mice into the central nervous system using fluorescent latex micro- that are doubly mutant in endothelial and neuronal nitric oxide spheres, BioTechniques 23 (1997) 928–934. synthase, Cell. 87 (1996) 1015–1023.

[127] C.D. Rittenhouse, H.Z. Shouval, M.A. Paradiso, M. Bear, Monocu- [147] G.S. Stent, A physiological mechanism for Hebb’s postulate of lar deprivation induces homosynaptic long-term depression in learning, Proc. Natl. Acad. Sci. USA 70 (1973) 997–1001. visual cortex, Nature 397 (1999) 347–350. [148] M.P. Stryker, W.A. Harris, Binocular impulse blockade prevents the [128] F.M. Rossi, Y. Bozzi, T. Pizzorusso, L. Maffei, Monocular formation of ocular dominance columns in cat visual cortex, J.

deprivation decreases brain-derived neurotrophic factor immuno- Neurosci. 6 (1986) 2117–2133.

reactivity in the rat visual cortex, Neuroscience 90 (1999) 363– [149] M.P. Stryker, S.L. Strickland, Physiological segregation of ocular

368. dominance columns depends on the pattern of afferent electrical

[129] E.S. Ruthazer, D.C. Gillespie, T.M. Dawson, S.H. Snyder, M.P. activity, Invest. Ophthalmol. Vis. Sci. 25 (1984) 278.

Stryker, Inhibition of nitric oxide synthase does not prevent ocular [150] H. Thoenen, Neurotrophins and neuronal plasticity, Science 270 dominance plasticity in kitten visual cortex, J. Physiol. (Lond.) 494 (1995) 593–598.

(1996) 519–527. [151] S. Van Wagenen, V. Rehder, Regulation of neuronal growth cone [130] N.B. Sawtell, K.M. Huber, J.C. Roder, M.F. Bear, Induction of filopodia by nitric oxide, J. Neurobiol. 39 (1999) 168–185.

NMDA receptor-dependent long-term depression in visual cortex [152] A. Vercelli, D. Garbossa, S. Biasiol, M. Repici, S. Jhaveri, NOS does not require metabotropic glutamate receptors, J. Neuro- inhibition during postnatal development leads to increased ipsila-physiol. 82 (1999) 3594–3597. teral retinocollicular and retinogeniculate projections in rats, Eur. J. [131] C.A. Scheiner, R.R. Mize, Cholinergic fiber patches in the mouse Neurosci. 12 (2000) 473–490.

superior colliculus develop normally in nitric oxide synthase gene [153] T. Wang, Z. Xie, B. Lu, Nitric oxide mediates activity-dependent deficient mice, Neurosci. Abs. 23 (1997) 1159. synaptic suppression at developing neuromuscular synapses, Na-[132] J.T. Schmidt, Long-term potentiation and activity-dependent re- ture 374 (1995) 262–266.

tinotopic sharpening in the regenerating retinotectal projection of [154] X. Wang, M.M. Poo, Potentiation of developing synapses by goldfish: common sensitive period and sensitivity to NMDA postsynaptic release of neurotrophin-4, Neuron 19 (1997) 825– blockers, J. Neurosci. 10 (1990) 233–246. 835.

(6)

[155] X. Wang, B. Berninger, M. M Poo, Localized synaptic actions of [159] H.H. Wu, R.J. Cork, D. Shuman, P.L. Huang, R.R. Mize, Refine-neurotrophin-4, J. Neurosci. 18 (1998) 4985–4992. ment of the ipsilateral retinocollicular projection is delayed in [156] J. Wood, J. Garthwaite, Models of the diffusional spread of nitric double endothelial and neuronal nitric oxide synthase gene

knock-oxide: implications for neural nitric oxide signalling and its out mice, Devel. Brain Res. 120 (2000) 105–111.

pharmacological properties, Neuropharmacology 33 (1994) 1234– [160] H.H. Wu, R.J. Cork, R.R. Mize, Development of the ipsilateral

1244. retinocollicular pathway in normal and NOS gene knockout mice,

[157] H.H. Wu, C.V. Williams, S.C. McLoon, Involvement of nitric oxide J. Comp. Neurol. (2000) in press.

in the elimination of a transient retinotectal projection in develop- [161] L.I. Zhang, T. Huizhong, H.W. Tao, C.E. Holt, W.A. Harris, M.M. ment, Science 265 (1994) 1593–1596. Poo, A critical window for cooperation and competition among [158] H.H. Wu, D.K. Waid, S.C. McLoon, Nitric oxide and the de- developing retinotectal synapses, Nature 395 (1998) 37–44.

velopmental remodeling of retinal connections in the brain, Prog. [162] J. Ziburkus, W. Guido, Long term synaptic depression in the Brain Res. 108 (1996) 273–286. developing LGN, Neurosci. Abs. 25 (1999) 1268.