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
2 +
dependence of striatal modification rules
The activity of PKC and CaMKII increases with Ca
2 +
enlargement, while cGMP concentra- tion and PKG activity are downregulated by
Ca
2 +
calmodulin Baltrons et al., 1997. So, Ca
2 +
entry through NMDA channels must influ- ence the ratio PKsPP1 in the dendritic spine of
the spiny striatal neuron as well as the efficacy of excitatory synaptic transmission Silkis, 2000c. If
NMDA channels are closed, Ca
2 +
rise and activ- ity of Ca
2 +
-dependent PKC and CaMKII can not be large, while PKG activity in the striatum is
initially high Surmeier et al., 1995. The role of PKA is possibly low, since cAMP can be hy-
drolyzed by highly effective cGMP-dependent PDE. The ratio PKGPP1 must strongly decrease
with Ca
2 +
rise Fig. 2a, left part of curve, since a lowering PKG activity is followed by enlarge-
ment of PP1 activity see Fig. 1. If NMDA channels are opened, high Ca
2 +
elevation can be
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
