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The Journal of Neurophysiology Vol. 83 No. 3 March 2000, pp. 1167-1180
Copyright ©2000 by the American Physiological Society
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
Takahashi, Kanji A. and
David J. Linden.
Cannabinoid Receptor Modulation of Synapses Received by
Cerebellar Purkinje Cells. J. Neurophysiol. 83: 1167-1180, 2000. The high density of cannabinoid receptors in
the cerebellum and the degradation of motor coordination produced by
cannabinoid intoxication suggest that synaptic transmission in the
cerebellum may be strongly regulated by cannabinoid receptors.
Therefore the effects of exogenous cannabinoids on synapses received by Purkinje cells were investigated in rat cerebellar slices. Parallel fiber-evoked (PF) excitatory postsynaptic currents (EPSCs)
were strongly inhibited by bath application of the cannabinoid receptor agonist WIN 55212-2 (5 µM, 12% of baseline EPSC amplitude). This effect was completely blocked by the cannabinoid CB1 receptor antagonist SR 141716. It is unlikely that this was the result of
alterations in axonal excitability because fiber volley velocity and
kinetics were unchanged and a cannabinoid-induced decrease in fiber
volley amplitude was very minor (93% of baseline). WIN 55212-2 had no effect on the amplitude or frequency of spontaneously occurring
miniature EPSCs (mEPSCs), suggesting that the effect of CB1 receptor
activation on PF EPSCs was presynaptically expressed, but giving no
evidence for modulation of release processes after Ca2+
influx. EPSCs evoked by climbing fiber (CF) stimulation were less
powerfully attenuated by WIN 55212-2 (5 µM, 74% of baseline). Large,
action potential-dependent, spontaneously occurring inhibitory postsynaptic currents (sIPSCs) were either severely reduced in amplitude (<25% of baseline) or eliminated. Miniature IPSCs
(mIPSCs) were reduced in frequency (52% of baseline) but not in
amplitude, demonstrating suppression of presynaptic vesicle release
processes after Ca2+ influx and suggesting an absence of
postsynaptic modulation. The decrease in mIPSC frequency was not large
enough to account for the decrease in sIPSC amplitude, suggesting that
presynaptic voltage-gated channel modulation was also involved. Thus,
while CB1 receptor activation reduced neurotransmitter release at all major classes of Purkinje cell synapses, this was not accomplished by a
single molecular mechanism. At excitatory synapses, cannabinoid suppression of neurotransmitter release was mediated by modulation of
voltage-gated channels in the presynaptic axon terminal. At inhibitory
synapses, in addition to modulation of presynaptic voltage-gated
channels, suppression of the downstream vesicle release machinery also
played a large role.
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