knowledge of the role of cerebellum in motor learning allowed elaboration of a neuronal model
of learning Ito, 1984; Houk et al., 1996; Clark et al., 1997; Kenyon, 1997; Mauk and Donegan,
1997; Raymond and Lisberger, 1997. The Marr – Albus – Ito model of cerebellum-dependent learn-
ing is based on only one type of synaptic plasticity: associative long-term depression of ex-
citatory transmission LTDe in synaptic path- ways between parallel fibers PFs and Purkinje
cells PCs Marr, 1969; Albus, 1971; Ito, 1984. The induction of this LTDe requires a pairing of
PFs and CF activation. Not only associative LTDe, but also homosynaptic LTDe and ho-
mosynaptic long-term potentiation of excitatory transmission LTPe have been recently found in
synapses formed by PFs on PCs Hartell, 1994. In addition, long-term depression of inhibitory
transmission LTDi between stellate or basket cells and PCs has been demonstrated Llano et al.,
1991; Kano et al., 1992. Only the mechanism of LTDe for PCs is described Linden, 1994; Daniel
et al., 1998; however, it is controversial. We have recently proposed the unitary postsynaptic mecha-
nism of excitatory and inhibitory synaptic plastic- ity
for the
neocortical, hippocampal
and cerebellar Purkinje cells Silkis, 1999. Using this
mechanism, one can predict the character of mod- ification of excitatory and inhibitory synapses on
diverse cells, if the types of postsynaptic recep- torschannels and second messenger are known.
Predicted results can be experimentally tested. The aim of this work has been to elucidate the
possible mechanisms and character of simulta- neous modifications in the efficacy of excitatory
and inhibitory synaptic inputs to different ele- ments of olivary-cerebellar neural network trig-
gered by rhythmic activation of MFs and CF.
2. The proposed mechanism of synaptic plasticity for Purkinje cells
Synaptic plasticity in different nervous struc- tures is considered as the result of changes in the
phosphorylation state of postsynaptic ionotropic AMPA, NMDA and GABAa receptors. Changes
in receptor phosphorylation could be caused by intracellular Ca
2 +
enlargement, variations in cyclic nucleotide cAMP or cGMP concentration
Fig. 1. The scheme of excitatory and inhibitory connections in olivary-cerebellar network. GC, Granule cell; Gol, Golgi cell; Lug, Lugaro cell; Sc, stellate cell; PC, Purkinje cell; DNe and DNi, excitatory and inhibitory deep cerebellar nuclei cells; RN, red nuclei;
In, input.
Fig. 2. The proposed consequence of post-tetanic processes, causing modification of synaptic inputs to cerebellar Purkinje
cell, granule cell, deep cerebellar nuclei cell. VDCC, voltage- dependent Ca
2 +
channel. mGlu, metabotropic glutamate re- ceptor; CaM, calmodulin; PKC, protein kinase C; PKG,
protein kinase G; CaMKII, Ca
2 +
calmodulin-dependent protein kinase II; PP2B, calcineurin; G-sub, G substrate-
inhibitor of protein phosphatases 1, PP1.
causes cerebellar LTDe. However, this assump- tion is inconsistent with some of the experimental
data Daniel et al., 1998. Moreover, it means that properties of AMPA receptors on PCs and
hippocampalneocortical neurones are different, since LTDe in hippocampalneocortical neurones
is the result of AMPA receptor dephosphoryla- tion Bear and Malenka, 1994. In PCs, LTDe
and LTPi have been observed when Ca
2 +
level was high, while moderate Ca
2 +
rise resulted in LTPe and LTDi Hirano, 1990; Hartell, 1994;
Kasono and Hirano, 1994; Linden, 1994. The Ca
2 +
dependence of the character of synaptic modification in the neocorticalhippocampal neu-
rones is opposite Bear and Malenka, 1994; Ko- matsu, 1996. However, the commonly accepted
idea of PC plasticity does not explain this distinction.
The suggested unitary postsynaptic mechanism of plasticity is based on our postulate that pro-
perties of AMPA receptors as well as GABAa receptors are similar in PCs and hippocampal
neocortical neurones Silkis, 1999. Therefore, phosphorylation dephosphorylation of AMPA
receptors leads to LTPe LTDe in PCs. The validity of this postulate is supported by the data
that artificial activation of PKC, which must lead to additional phosphorylation of receptors, causes
LTPe for the most part of PCs Crepel and Jail- lard,
1991. Analogously,
phosphorylation dephosphorylation of GABAa receptors results
in LTDi LTPi in both, hippocampalneocortical cells and PCs. This assumption is also experimen-
tally supported Pasqualotto et al., 1993. In addi- tion,
we have
proposed that
activation of
metabotropic GABAb receptors, which causes a changes in the concentration of intracellular Ca
2 +
and cyclic nucleotide, is required for input-specific modification of inhibitory synapses Silkis, 1997.
The necessity of GABAb receptors for the induc- tion of LTPi has been recently demonstrated in
the neocortex Komatsu, 1996.
Signal transduction processes proposed to par- ticipate in cerebellar plasticity are schematically
presented in Fig. 2. We have assumed that the involvement of cGMP and cAMP in synaptic
plasticity of PCs and hippocampalneocortical and subsequent changes in the activity of protein
kinases and protein phosphatases Ito and Kara- chot, 1992; Bear and Malenka, 1994; Linden,
1994; Daniel et al., 1998. Receptors can be phos- phorylated by cAMP-dependent protein kinase A
PKA,
cGMP-dependent protein
kinase G
PKG, protein kinase C PKC and Ca
2 +
calmodulin dependent
protein kinase
II CaMKII, and dephosphorylated by protein
phosphatase 1. The rise of Ca
2 +
concentration is provided by its influx through voltage-dependent
Ca
2 +
channels VDCCs after the depolarization of postsynaptic cell, and by its efflux from intra-
cellular Ca
2 +
stores after metabotropic glutamate mGlu receptor activation Bear and Malenka,
1994. Activation of mGlu receptors leads also to an increase in the activity of PKC and PKA
Linden, 1994; Breakwell et al., 1998.
According to current opinion, distinctive mech- anisms underlie excitatory synaptic plasticity in
cerebellar PCs and hippocampalneocortical neu- rones Ito and Karachot, 1992; Linden, 1994;
Daniel et al., 1998. It is believed that phosphory- lation of AMPA receptors by PKC and PKG
cells, respectively, underlies the opposite Ca
2 +
-de- pendent modification rules for these structures
Silkis, 1999. This assumption is based on the data that cGMP concentration is down-regulated
by Ca
2 +
calmodulin Baltrons et al., 1997, while the increase in cAMP level is positively correlated
with Ca
2 +
rise. We have proposed that the rise in cGMP level could be provided not only by NO
action on soluble guanylate cyclase Linden, 1994; Daniel et al., 1998, but also by the activation of
membrane-bound guanylate cyclase via GABAb receptors Silkis, 1998. Our preliminary experi-
mental data support this hypothesis Silkis et al., 1998.
To provide the fulfillment of the Hebbian rule, we have postulated that only receptors activated
by a transmitter are modifiable. This postulate corresponds with the data that artificial rise of
intracellular Ca
2 +
level or increase in protein kinase activity does not lead to a change in phos-
phorylation state to LTP or LTD in the absence of synaptic activation Nakazawa et al., 1995;
Otsu et al., 1995; Wu et al., 1998. Using the computational model of postsynaptic processes,
we have found that the Hebbian rule the coinci- dence of pre- and postsynaptic cell activity is the
only necessary condition for synaptic plasticity. Modification of simultaneously activated excita-
tory and inhibitory inputs, such as LTPe together with LTDi, or LTDe together with LTPi can be
obtained only due to variations in pre- andor postsynaptic cell activity. The sign of modification
LTP or LTD is determined by the shift positive or negative in the ratio between active protein
kinases and phosphatases in relation to the ratio produced by prior stimulation Silkis, 1998.
3. Necessary conditions for the modifications of synapses on different cerebellar cells
