Such forms of plasticity as long-term potentiation LTP and long-term depression LTD in the
efficacy of excitatory transmission, and inhibitory transmission LTPi, LTDi, have been obtained in
the neocortex, hippocampus, cerebellum, basal ganglia and other structures of the central ner-
vous system CNS. It has been found that Ca
2 +
- dependent changes in the activity of protein
kinases PKs and protein phosphatase 1 PP1 are necessary for synaptic modification in these
structures Calabresi et al., 1992, 1994, 1999b; Bear and Malenka, 1994; Pisani et al., 1997;
Daniel et al., 1998. The relatively highlow post- synaptic Ca
2 +
elevation usually causes neocorti- cal or hippocampal LTPLTD and cerebellar
LTDLTP Bear and Malenka, 1994; Hartell, 1994. In the neocortex or hippocampus cerebel-
lum, LTDi induction requires an additional Ca
2 +
lowering elevation compared with the Ca
2 +
level that causes LTPi for a review, see Silkis, 1998. Therefore, Ca
2 +
-dependent modifi- cation rules for excitatory and inhibitory synapses
are opposite. We have explained the diverse Ca
2 +
-dependent modification rules for the neocortical hippocampal and cerebellar cells by expression of
different cyclic nucleotides, cAMP and cGMP, respectively Silkis, 2000a,b.
In the striatum, the input structure of the basal ganglia, experimentally observed Ca
2 +
depen- dence of LTP and LTD looks contradictory. On
the one hand, it has been demonstrated that the highlow Ca
2 +
elevation is required for LTD LTP Calabresi et al., 1992, 1994. On the other,
LTP induction had been facilitated by diverse protocols that led to additional Ca
2 +
rise Cal- abresi et al., 1997; Pisani et al., 1997. The mecha-
nism explaining
these controversial
results remains unknown. In addition, the sign of synap-
tic modification in the striatum essentially de- pends on the activation of different types of
receptors sensitive to dopamine, adenosine and acetylcholine Calabresi et al., 1994, 1997, 1999a;
Hernandes-Lopez et al., 1997. However, the mechanism of participation of these modulatory
neurotransmitters in striatal plasticity is not clearly understood.
The aim of this work has been to analyze the possible mechanisms underlying experimentally
found features of striatal LTPLTD. We analyzed the role of NMDA receptor activation in the
Ca
2 +
dependence on the sign of synaptic modifi- cation and modulatory role of dopamine D
1
D
2
, adenosine A
1
A
2A
and acetylcholine muscarinic M
1
M
4
receptor activation in synaptic plasticity. An earlier suggested unitary postsynaptic mecha-
nism of plasticity Silkis, 1998, 2000a,b provided the basis for this analysis.
2. The proposed mechanism for synaptic plasticity in striatal spiny cells
Different PKs phosphorylate ionotropic AMPA responsive
to a
-amino-3-hydroxy-5-methyl-4- isoxazolepropionate and NMDA sensitive to N-
methyl-
D
-aspartate receptors, increasing their sensitivity to glutamate Fig. 1. In the striatal
spiny cells, AMPA and NMDA receptors can be phosphorylated by cAMP-dependent protein ki-
nase A PKA, cGMP-dependent protein kinase G PKG, Ca
2 +
calmodulin-dependent protein kinase II CaMKII and protein kinase C PKC,
and can be dephosphorylated by PP1 Calabresi
Fig. 1. The proposed consequence of post-tetanic processes, causing modification of synaptic inputs to the striatal medium
spiny cell. VDCC and GPCC, voltage-dependent and G- protein-coupled Ca
2 +
channels; GPKC, G-protein-coupled K
+
-channels; mGlu, metabotropic glutamate receptor; CaM, calmodulin; PKA, PKG, PKC protein kinases A, G, C;
CaMKII, Ca
2 +
calmodulin-dependent protein kinase II; PP2B, calcineurin; DARPP-32, inhibitor of protein phos-
phatase 1, PP1; PDE, phosphodiesterase; arrow, increase; rhomb, decrease.
et al., 1994, 1999b; Snyder et al., 1998; Oh et al., 1999; Yan et al., 1999. Since the same protein
kinases PKA, PKC, CaMKII, PKG also phos- phorylate
GABA
A
receptors, decreasing
in- hibitory transmission McDonald and Moss,
1997, the sign of modification of the inhibitory synapse must be opposite to that of the adjacent
excitatory synapse.
Synaptically induced changes in the Ca
2 +
con- centration, and activity of PKs and PP1 in striatal
spiny cells are provided by activation of different receptors Fig. 1. The opening NMDA channels
strongly increase the postsynaptic Ca
2 +
concen- tration. The activation of metabotropic glutamate
mGlu receptors leads to Ca
2 +
elevation and activation of PKC, CaMKII and Ca
2 +
calmod- ulin-dependent protein phosphatase 2B PP2B.
An activation of GABA
B
receptors results in a lowering the Ca
2 +
and cAMP level Hashimoto and Kuriyama, 1997. In the striatal spiny cells,
wherein adenylate cyclase is Ca
2 +
calmodulin in- dependent Polli and Kincaid, 1994, an activation
of dopamine-sensitive
D
1
D
2
receptors or
adenosine-sensitive A
2A
A
1
receptors causes an increasedecrease in cAMP concentration Collis
and Hourani, 1993; Snyder et al. 1998. In addi- tion, D
2
receptor activation causes a decrease of Ca
2 +
influx Strange, 1993. Activation of acetyl- choline muscarinic M
1
or M
3
receptors causes Ca
2 +
efflux from intracellular stores and an in- crease in PKC activity de la Vega et al., 1997,
while an activation of muscarinic M
4
or M
2
recep- tors leads to a decrease in cAMP concentration
Olianas et al., 1996. Conjunctive action on mGlu and A
2A
receptors increases cAMP accumu- lation, while activation of mGlu and D
1
receptors decreases cAMP level Wang and Johnson, 1995.
The elevating cGMP concentration in striatal spiny cells is believed to be the result of nitric
oxide NO action on soluble guanylate cyclase Calabresi et al., 1999b. However, NO synthase is
expressed in the axon terminals of striatal in- terneurons Calabresi et al., 1999b, the number
of which is very small, while cGMP concentration is high Surmeier et al., 1995. We hypothesized
that cGMP elevation could be also caused by activation of membrane-bound guanylate cyclase
through GABA
B
receptors Silkis, 2000a,b. Such effect we have obtained in the cerebellar cortex.
The activity of PP1 in the striatum is controlled by its inhibitor DARPP-32, which is phosphory-
lated by PKA and PKG and dephosphorylated by PP2B Snyder et al., 1998; Greengard et al., 1999.
The supposed sequence of interconnected bio- chemical processes in the dendritic spine of a
striatal neuron underlying postsynaptic mecha- nisms of excitatory and inhibitory synaptic plas-
ticity Fig. 1, to a large extent, is similar to those we earlier suggested for the neocorticalhippocam-
pal pyramidal cells and Purkinjedeep cerebellar nuclei cells Silkis, 2000a,b. Using a computa-
tional model of post-tetanic biochemical processes in the dendritic spine of a pyramidal cell, we have
found that the efficacy of the excitatory synaptic transmission, which is proportional to the number
of phosphorylated AMPA and NMDA receptors, depends on the ratio PKsPP1 Silkis, 1998,
2000a. This ratio is strongly affected by post- tetanic Ca
2 +
elevation and completely defined by parameters of stimulation. The necessary condi-
tion for synaptic modification is a post-tetanic shift in the ratio PKsPP1 in relation to the value
produced by previous stimulation Silkis, 1998, 2000a.
According to the current view, phosphorylation of AMPA receptors by PKC and PKG may un-
derlie striatal and cerebellar LTD Calabresi et al., 1994, 1999b; Nakazawa et al., 1995. We have
pointed out Silkis, 2000a,b that such mechanism of LTD implies that properties of AMPA recep-
tors on striatal or cerebellar cells are distinctive from those on hippocampal or neocortical cells,
wherein
AMPA receptor
phosphorylation dephosphorylation underlies LTPLTD Bear and
Malenka, 1994. We have postulated that sensitiv- ity of the same type of receptors in different CNS
structures identically depends on their phosphory- lation Silkis, 2000a. Therefore, the striatal LTP
LTD LTDiLTPi must be the consequence of an increasedecrease in the number of highly low
sensitive phosphorylated AMPA and NMDA GABA
A
receptors. The suggested postulate for striatal plasticity is
supported by data that LTPLTD in this structure correlates with phosphorylating action of PKA,
PKC and CaMKII and dephosphorylating action
Fig. 2. The influence of neuromodulators on the efficacy of excitatory synaptic transmission. a Influence of inhibition on the efficacy of excitatory synaptic input; solid line, the proposed dependence of the ratio PKsPP1 that determine synaptic efficacy on
postsynaptic Ca
2 +
elevation for activation of excitatory input alone; dotted line, additional activation of GABA
B
receptors; Ca
2 + 0i
or Ca
2 + 0k
and Ca
2 + P
, a Ca
2 +
rise produced by diverse prior activation and current stimulation, respectively. b Influence of dopamine, adenosine and acetylcholine on NMDA-dependent modification of excitatory synaptic input; dashed line, activation of
D
1
or A
2A
receptors; dash – dotted line, activation of D
2
or A
1
receptors, dash – double dotted line, activation of M
1
or M
3
receptors; dotted line, activation of M
4
or M
2
receptors.
of PP1 Stefani et al., 1995; Hernandes-Lopez et al., 1997; Pisani et al., 1997; Snyder et al., 1998; Martin
et al., 1999; Oh et al., 1999. LTP was obtained instead of LTD after increasing the concentration
of phosphodiesterase PDE inhibitor Calabresi et al., 1999b. This protocol causes an increase in the
ratio PKsPP1 due to a rising the cyclic nucleotide concentration see Fig. 1. Phosphorylation also
resulted in an augmentation of the efficacy of striatal voltage-dependent Ca
2 +
channels VD- CCs, while an inhibition of PKG reduced the
Ca
2 +
current through VDCCs Trautwein and Hescheier, 1990; Surmeier et al., 1995. On the
contrary, it was found that LTDiLTPi in the basal ganglia correlates with phosphorylationdephos-
phorylation of GABA
A
receptors by PKA and PKCPP1. A decrease of the current through
GABA
A
receptors due to PKA activation andor PP1 inhibition has been found not only in striatal
spiny cells, but also in cholinergic interneurons and dopamine neurons of the ventral tegmental area
Bonci et al., 1997; Yan and Surmeier, 1997; Flores-Hernandez et al., 2000.
3. The proposed role of NMDA receptor activation in the Ca
