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Volume 16, Number 9,
Issue of May 1, 1996
pp. 2881-2890
Copyright ©1996 Society for Neuroscience
Inhibition of cGMP Breakdown Promotes the Induction of Cerebellar
Long-Term Depression
Received Aug. 8, 1995; revised Feb. 1, 1996; accepted Feb. 5, 1996.
Nick A. Hartell
Laboratory for Synaptic Function, Frontier Research Program, RIKEN,
Wako-shi, Saitama, 351-01, Japan
The effects of the nonspecific cyclic nucleotide inhibitors
1-methyl-3-isobutylxanthine (IBMX) and dipyridamole, and the
cGMP-specific phosphodiesterase inhibitor Zaprinast were studied on
parallel fiber-Purkinje cell synaptic responses in rat cerebellar
slices. Bath application of all three compounds, at concentrations
shown to inhibit cGMP breakdown, led to stable and robust long-term
depression of PF responses. Injections of dipyridamole directly into
the Purkinje cell dendrites were similarly effective as bath
applications, confirming a postsynaptic site of action. Inhibitors of
both protein kinase G and C and also the metabotropic glutamate
receptor antagonist MCPG completely prevented the induction of LTD by
dipyridamole and Zaprinast. The extent of phosphodiesterase-induced
synaptic depression was dependent on the frequency of parallel fiber
stimulation, and this form of LTD both occluded and was occluded by LTD
induced by pairing parallel and climbing fiber inputs. The degree of
LTD induced by IBMX was dose-dependent, and also required PKC and PKG
activity, but was preceded by a large, transient potentiation of
parallel fiber responses occurring by a postsynaptic mechanism
independent of cGMP. These data not only confirm that cGMP is capable
of inducing cerebellar LTD when paired with parallel fiber stimulation
but indicate that cGMP is an endogenous intermediate in this form of
synaptic plasticity.
Key words:
cGMP;
phosphodiesterase inhibitor;
cerebellum;
Purkinje
cell;
long-term depression;
climbing fiber
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