Cannabinoids decrease excitatory synaptic transmission and impair long‐term depression in rat cerebellar Purkinje cells

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Abstract
CB‐1 cannabinoid receptors are strongly expressed in the molecular layer of the cerebellar cortex. We have analysed, in patch‐clamped Purkinje cells (PCs) in rat cerebellar slices, the effect of the selective CB‐1 agonists WIN55,212‐2 and CP55,940 and of the selective CB‐1 antagonist SR141716‐A on excitatory synaptic transmission and synaptic plasticity. Bath application of both agonists markedly depressed parallel fibre (PF) EPSCs. This effect was reversed by SR141716‐A. In contrast, responses of PCs to ionophoretic application of glutamate were not affected by WIN55,212‐2. The coefficient of variation and the paired‐pulse facilitation of these PF‐mediated EPSCs increased in the presence of WIN55,212‐2. WIN55,212‐2 decreased the frequency of miniature EPSCs and of asynchronous synaptic events evoked in the presence of strontium in the bath, but did not affect their amplitude. WIN55,212‐2 did not change the excitability of PFs. WIN55,212‐2 impaired long‐term depression induced by pairing protocols in PCs. This effect was antagonized by SR141716‐A. The same impairment of LTD was produced by 2‐chloroadenosine, a compound that decreases the probability of release of glutamate at PF‐PC synapses. The present study demonstrates that cannabinoids inhibit synaptic transmission at PF‐PC synapses by decreasing the probability of release of glutamate, and thereby impair LTD. These two effects might represent a plausible cellular mechanism underlying cerebellar dysfunction caused by cannabinoids.