Sexually Dimorphic Adolescent Trajectories of Prefrontal Endocannabinoid Synaptic Plasticity Equalize in Adulthood, Reflected by Endocannabinoid System Gene Expression.

How sex influences prefrontal cortexes (PFCs) synaptic development through adolescence remains unclear. In this study we describe sex-specific cellular and synaptic trajectories in the rat PFC from adolescence to adulthood. The excitability of PFC layer 5 pyramidal neurons was lower in adult females compared with other developmental stages. The developmental course of endocannabinoid-mediated long-term depression (eCB-LTD) was sexually dimorphic, unlike long-term potentiation or mGluR3-LTD. eCB-LTD was expressed in juvenile females but appeared only at puberty in males. Endovanilloid TRPV1R or eCB receptors were engaged during LTD in a sequential and sexually dimorphic manner. Gene expression of the eCB/vanilloid systems was sequential and sex specific. LTD-incompetent juvenile males had elevated expression levels of the CB1R-interacting inhibitory protein cannabinoid receptor interacting protein 1a and of the 2-arachidonoylglycerol-degrading enzyme ABHD6. Pharmacological inhibition of ABHD6 or MAGL enabled LTD in young males, whereas inhibition of anandamide degradation was ineffective. These results reveal sex differences in the maturational trajectories of the rat PFC.