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The Journal of Neurophysiology Vol. 82 No. 3 September 1999, pp. 1286-1294
Copyright ©1999 by the American Physiological Society
Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, California 92037
Sullivan, Jane M.
Mechanisms of Cannabinoid-Receptor-Mediated Inhibition of
Synaptic Transmission in Cultured Hippocampal Pyramidal Neurons. J. Neurophysiol. 82: 1286-1294, 1999. Cannabinoids, such as marijuana, are known to impair learning and
memory perhaps through their actions in the hippocampus where
cannabinoid receptors are expressed at high density. Although cannabinoid receptor activation decreases glutamatergic synaptic transmission in cultured hippocampal neurons, the mechanisms of this
action are not known. Cannabinoid receptor activation also inhibits
calcium channels that support neurotransmitter release in these cells,
making modulation of these channels a candidate for
cannabinoid-receptor-mediated effects on synaptic transmission. Whole
cell patch-clamp recordings of glutamatergic neurons cultured from the
CA1 and CA3 regions of the hippocampus were used to identify the
mechanisms of the effects of cannabinoids on synaptic transmission. Cannabinoid receptor activation reduced excitatory postsynaptic current
(EPSC) size by ~50% but had no effect on the amplitude of
spontaneous miniature EPSCs (mEPSCs). This reduction in EPSC size was
accompanied by an increase in paired-pulse facilitation measured in low
(1 mM) extracellular calcium and by a decrease in paired-pulse
depression measured in normal (2.5 mM) extracellular calcium. Together,
these results strongly support the hypothesis that cannabinoid receptor
activation decreases EPSC size by reducing release of neurotransmitter
presynaptically while having no effect on postsynaptic sensitivity to
glutamate. Further experiments were done to identify the molecular
mechanisms underlying this cannabinoid-receptor-mediated decrease in
neurotransmitter release. Cannabinoid receptor activation had no effect
on the size of the presynaptic pool of readily releasable
neurotransmitter-filled vesicles, eliminating reduction in pool size as
a mechanism for cannabinoid-receptor-mediated effects. After blockade
of Q- and N-type calcium channels with 
-agatoxin TK and
-conotoxin GVIA; however, activation of cannabinoid receptors
reduced EPSC size by only 14%. These results indicate that cannabinoid
receptor activation reduces the probability that neurotransmitter will be released in response to an action potential via an inhibition of
presynaptic Q- and N-type calcium channels. This molecular mechanism
most likely contributes to the impairment of learning and memory
produced by cannabinoids and may participate in the analgesic,
antiemetic, and anticonvulsive effects of these drugs as well.
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