Smith_2025_eNeuro__

The endocannabinoid (eCB) signaling system is robustly expressed in the cerebellum from embryonic developmental stages to adulthood. It plays a key role in regulating cerebellar synaptic plasticity and excitability, suggesting that impaired eCB signaling could lead to deficits in cerebellar adjustments of ongoing behaviors and cerebellar learning. Indeed, human mutations in DAGLalpha are associated with neurodevelopmental disorders. In this study, we show that selective deletion of the eCB synthesizing enzyme diacylglycerol lipase alpha (Daglalpha) from mouse cerebellar Purkinje cells (PCs) alters motor and social behaviors, disrupts short-term synaptic plasticity in both excitatory and inhibitory synapses, and reduces PC activity during social exploration. Our results provide the first evidence for cerebellar-specific eCB regulation of social behaviors and implicate eCB regulation of synaptic plasticity and PC activity as the neural substrates contributing to these deficits.Significance statement Deletion of the endocannabinoid synthesizing enzyme diacylglycerol lipase alpha (Daglalpha) from mouse cerebellar Purkinje cells alters motor and social behaviors, disrupts short-term synaptic plasticity, and reduces Purkinje cell activity during social exploration.