Brief presynaptic bursts evoke synapse-specific retrograde inhibition mediated by endogenous cannabinoids

Abstract

Many types of neurons can release endocannabinoids that act as retrograde signals to inhibit neurotransmitter release from presynaptic terminals. Little is known, however, about the properties or role of such inhibition under physiological conditions. Here we report that brief bursts of presynaptic activity evoked endocannabinoid release, which strongly inhibited parallel fiber-to-Purkinje cell synapses in rat cerebellar slices. This retrograde inhibition was triggered by activation of either postsynaptic metabotropic or ionotropic glutamate receptors and was restricted to synapses activated with high-frequency bursts. Thus, endocannabinoids allow neurons to inhibit specific synaptic inputs in response to a burst, thereby dynamically fine-tuning the properties of synaptic integration.

Cannabis Use Disrupts Eyeblink Conditioning: Evidence for Cannabinoid Modulation of Cerebellar-Dependent Learning

“…In regard to cannabinoid modulation of this circuit, CB1 receptors are known to reside on glutamatergic granule cell axons (parallel fiber terminals). Purkinje cells synthesize and release retrograde endocannabinoids following bursts of parallel fiber stimulation (Brown et al, 2003). Thus, during EBC, endocannabinoids may operate by activating presynaptic CB1 receptors on parallel fiber terminals, which reduce Ca 2 + influx, ultimately inhibiting Purkinje cell activity by decreasing glutamate release from parallel fiber terminals.…”

Fatty Acid Amide Hydrolase Inhibition by JNJ‐42165279: A Multiple‐Ascending Dose and a Positron Emission Tomography Study in Healthy Volunteers

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Cannabinoids and Epilepsy

“…1). Depolarization of the postsynaptic cell or direct activation of metabotropic glutamate receptors increases levels of intracellular calcium, which trigger second messenger cascades that promote endocannabinoid synthesis [35][36][37][38][39]. Anandamide is synthesized via phospholipase D-mediated hydrolysis of N-arachidonoylphosphatidylethanolamine, and degraded by the fatty acid amide hydrolase (FAAH) into arachidonic acid and ethanolamine [40][41][42][43].…”