achieved and the activity of PKG becomes negli- gible. In this case, PKC and CaMKII must play
the significant role in the ratio PKsPP1 Fig. 2a, right part of curve. Actually, NMDA-dependent
LTP has been induced without PKG activation Calabresi et al. 1999b. It is obvious from the
curve in Fig. 2a that the positivenegative postsy- naptic Ca
2 +
shift must cause increasedecrease in synaptic efficacy if NMDA channels are opened
NMDA-dependent LTPLTD, and decreasein- crease in synaptic efficacy if NMDA channels are
closed NMDA-independent LTPLTD. Thus, modification rules for NMDA-dependent and
NMDA-independent synaptic plasticity in the striatum are opposite Table 1. In terms of the
proposed mechanism, this effect is the result of involving PKG and PKA + PKC + CaMKII in
NMDA-independent and NMDA-dependent ef- fects, respectively. Thus, non-unique striatal mod-
ification
rules that
look like
neocorticalhippocampal cerebellar modification rules, if NMDA channels are opened closed,
could be the sequence of involving cAMP cGMP in the postsynaptic cascades.
The diverse modification rules in the striatum manifest itself in experiments performed in vitro
and in vivo. In normal striatal slices, EPSP usu- ally consists of the AMPA component only, while
both AMPA
and NMDA
components are
recorded in vivo Calabresi et al., 1994. In agree- ment with suggested modification rules, an artifi-
cial elevatinglowering of the intracellular Ca
2 +
concentration in striatal slices resulted in NMDA- independent LTDLTP Calabresi et al., 1992,
1994; Dos-Santos-Villar and Walsh, 1999. The Ca
2 +
influx through NMDA channels reversed Ca
2 +
dependence of the sign of synaptic modifi- cation in the striatum Calabresi et al., 1992,
1997. In experiments in vivo, any one protocol that had augmented Ca
2 +
concentration andor protein kinase activity facilitated NMDA-depen-
dent LTP in spiny striatal cells Charpier and Deniau, 1997; Pisani et al., 1997. It must be
noted that the same stimulation protocol, which leads to the same post-tetanic Ca
2 +
elevation, may result in LTP LTD, if this concentration
exceeds is less than a Ca
2 +
rise produced by prior stimulation, Ca
2 + 0i
Ca
2 + 0k
Fig. 2a. There- fore, both LTP and LTD could be obtained in
adjacent cells after tetanization. Such an effect has been observed in spiny striatal neurons Dos-San-
tos-Villar and Walsh, 1999. The firing rate of corticostriatal neurons can exceed 100 Hz Cal-
abresi et al., 1992. Thus, the usually used parameters
of rhythmic
stimulation are
physiological.
4. Influence of GABA, dopamine, adenosine and acetylcholine on the sign and magnitude of
synaptic modification
It follows from the suggested mechanism of plasticity that a decrease in Ca
2 +
and cAMP concentration due to GABA
B
receptor activation must lead to reducing PKA activity and lowering
the number of phosphorylated AMPA and NMDA receptors Fig. 2a, dashed line, right part
of curve. This effect leads to NMDA-dependent LTD. If NMDA channels are closed, the addi-
tional activation of GABA
B
receptors must facili- tate
NMDA-independent LTP
due to
the enlargement of PKG activity and rising the ratio
PKGPP1 Fig. 2a, dashed line, left part of curve. An activation of D
1
D
2
receptors or A
2A
A
1
re- ceptors can also result in risingdecreasing PKA
activity and subsequent elevatinglowering of the ratio PKsPP1 in striatal spiny cells Fig. 2b,
dasheddash – dotted line. For this reason, an ad- ditional activation of D
1
or A
2A
receptors must increase the magnitude of NMDA-dependent
LTP and LTDi, while an activation of D
2
or A
1
receptors can decrease these effects Table 1 or even reverse NMDA-dependent LTP into LTD
and LTDi into LTPi. On the contrary, a blockade of D
2
or A
1
receptors must promote NMDA-de- pendent LTP together with LTDi that can appear
in a rising cell activity. Indeed, in experiments in vivo, the administration of a D
2
receptor antago- nist resulted in the increase in bursting activity of
synaptically excited striatal cells Finch, 1999. Activation of D
1
receptors resulted in LTP of excitatory transmission Hernandes-Lopez et al.,
1997; Price et al., 1999 and depression of in- hibitory transmission Flores-Hernandez et al.,
2000. Activation of D
2
receptors led to inverting
I. Silkis
BioSystems
57 2000
187 –
196
Table 1 Modification rules for cortico-striatal synaptic plasticity and influence of neuromodulators on NMDA-dependent effects
The sign of post-tetanic modification of Modification of synaptically activated excitatory and inhibitory inputs after
Post-tetanic Ca
2+
shift in additional activation of receptors, sensitive to diverse modulatory neurotransmitters,
relation to Ca
2+
rise produced excitatory and inhibitory inputs
by previous stimulation if NMDA channels are opened
a
NMDA channels Dopamine-sensitive
Adenosine-sensitive NMDA
Acetylcholine-sensitive muscarinic receptors
closed receptors
channels open receptors
A
1
M
1
M
3
M
4
M
2
D
1
D
2
A
2A
LTP Ca
2+
\ Ca
2+
LTD LTP
LTP LTD
LTP LTD
LTD LTP
Ca
2+
B Ca
2+
LTD Ca
2+
\ Ca
2+
LTPi LTPi
LTDi LTPi
LTDi LTDi
LTPi LTDi
LTPi Ca
2+
B Ca
2+
LTDi
a
The sign of modification could be reversed after the blockade of receptors, sensitive to diverse modulatory neurotransmitters. LTPLTD, Long-term potentiationdepression of excitatory transmission; LTPiLTDi, long-term potentiationdepression of inhibitory transmission.
LTP into LTD, while D
2
receptor inactivation resulted in the enhancement of LTP Calabresi et
al., 1997. On the other hand, activation of D
2
receptors can facilitate NMDA-independent LTP as well as NMDA-independent LTDi due to de-
creasing Ca
2 +
concentration and subsequent ris- ing PKG activity. Actually, in the presence of
AMPA and NMDA receptor blockators, an inhi- bition of GABAergic synaptic response in striatal
cells has been obtained after D
2
receptor activa- tion Delgado et al., 1999. A
2A
receptor activa- tion inactivation that leads to a rise decrease in
PKA activity also resulted in striatal LTDi LTPi Mori et al., 1996. A depressive facilitating
action of A
2A
receptor agonist antagonist on inhibition of striatal cell firing mediated by D
2
receptor agonist has been shown previously Stromberg et al., 1998.
Experimental data supporting the proposed role of adenosine in synaptic plasticity have been
mostly obtained in the hippocampus. A blockade of A
2
receptors resulted in the preventing LTP and augmentation of depotentiation or LTD
Kessey et al., 1997; Fujii et al., 1999. A depoten- tiation produced by adenosine has been shown to
be the consequence of a decrease in PKA activity Huang et al., 1999. This result is in accordance
with our conclusion that the same mechanism dephosphorylation underlies both LTD and de-
potentiation Silkis, 1998. On the contrary, a blockade of A
1
receptors caused a facilitating LTP and decreasing depotentiation Fujii et al.,
1999. However, an activation of A
1
receptors augmented depotentiation and prevented LTP
Hogan et al., 1998. In terms of the suggested mechanism, an activa-
tion of M
1
or M
3
receptor and a subsequent increase in Ca
2 +
concentration and PKC activity Fig. 2b, dash – double dotted line must promote
NMDA-dependent LTP and LTDi. Oppositely, an activation of M
2
or M
4
receptors that causes lowering cAMP concentration and PKA activity
Fig. 2b, dotted line must facilitate NMDA-de- pendent LTD and LTPi. Indeed, an activation of
M
1
receptors as well as a blockade of M
2
recep- tors on striatal cells enhanced NMDA-dependent
LTP Calabresi et al., 1998a, 1999a. In addition, an activation of M
1
and M
3
receptors decreased the amplitude of inhibitory current in the spiny
cells Szabo et al., 1998, while an enhancement of GABA-activated current has been obtained after
activation of M
4
receptors Hu et al., 1999. The blockade of muscarinic receptors must cause the
opposite effects. One can expect that acetylcholine also
influences NMDA-independent
synaptic modification, since neuronal NO-synthase activity
and cGMP formation could be stimulated by M
1
receptor activation Wotta et al., 1998. However, in experimental conditions, no changes of AMPA
response has been found after M
1
receptor activa- tion Calabresi et al., 1998b. Possibly, the
amount of cGMP, produced through NO-stimu- lated cascade, is insufficient. The suggested
scheme of postsynaptic striatal processes Fig. 1 can be supplemented by those triggered by activa-
tion of other receptor types that cause changes in the ratio PKsPP1. For example, it follows from
the suggested mechanism that an activation of opiate m and d receptors, and subsequent inhibi-
tion of cAMP formation Greengard et al., 1999, may prevent LTP and promote LTD.
5. Conclusion
