Nat Commun 11, (2020) https://doi.org/10.1038/s41467-020-20121-3
1 Department of Cell Biology and Anatomy, LSU Health Sciences Center, New Orleans, LA 70112 USA.
2 Present address: Univ. Bordeaux, CNRS, EPHE, INCIA, UMR 5287, F-33000 Bordeaux, France.
3 Southeast Louisiana VA Healthcare System, New Orleans, Louisiana 70119, USA.
Co-first author
Endocannabinoids regulate many aspects of brain function by suppressing synaptic transmission via an on-demand release and activation of endocannabinoid receptors. A key regulator is the degradation process because this controls the temporal profile of endocannabinoid action. A fundamental question is whether endocannabinoid degradation plays a house-keeping role or is dynamically regulated by neuronal activity and thus actively participates in learning. Here we show that fear conditioning accelerates the degradation of endocannabinoids in the cerebellar cortex and this effect is driven by a learning-induced lasting increase in GABA release. Pharmacogenetic activation of cerebellar Purkinje cells after fear conditioning enhanced tonic endocannabinoid signaling and impaired cued memory retention via a CB1 receptor-mediated pathway. Therefore a learning-induced increase in GABA release accelerates 2-AG degradation in the cerebellum and drives the consolidation of fear memory. This novel form of degradation-dependent plasticity remodels synaptic integration and information processing within a neuronal circuit.
