Deletion of endocannabinoid synthesizing enzyme DAGLα from cerebellar Purkinje cells decreases social preference and elevates anxiety

Abstract

The endocannabinoid (eCB) signaling system is robustly expressed in the cerebellum starting from the embryonic developmental stages to adulthood. There it plays a key role in regulating cerebellar synaptic plasticity and excitability, suggesting that impaired eCB signaling will lead to deficits in cerebellar adjustments of ongoing behaviors and cerebellar learning. Indeed, human mutations in DAGL are associated with neurodevelopmental disorders. In this study, we show that selective deletion of the eCB synthesizing enzyme diacylglycerol lipase alpha (Dagl) from mouse cerebellar Purkinje cells (PCs) alters motor and social behaviors, disrupts short-term synaptic plasticity in both excitatory and inhibitory synapses, and reduces Purkinje cell 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. O_FIG O_LINKSMALLFIG WIDTH=173 HEIGHT=200 SRC="FIGDIR/small/607068v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@1a0a1d8org.highwire.dtl.DTLVardef@e17f34org.highwire.dtl.DTLVardef@665a75org.highwire.dtl.DTLVardef@1bcc7f1_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract.C_FLOATNO Cerebellar anatomy, morphology of Purkinje cells, localization, density, and spontaneous activity of excitatory and inhibitory synapses are normal in cerebellar-Purkinje-cell-specific Dagl KOs. However, endocannabinoid-dependent short-term synaptic plasticity (DSE and DSI) and activity of Purkinje cells in lobe VI during social exploration are dramatically reduced, and the KO mice exhibit alterations in sensorimotor coordination, deceased social preference, and increased anxiety. C_FIG