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

Introduction: How sex influences prefrontal cortexes (PFCs) synaptic development through adolescence remains unclear. Materials and Methods: In this study we describe sex-specific cellular and synaptic trajectories in the rat PFC from adolescence to adulthood. Results: 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. Conclusions: These results reveal sex differences in the maturational trajectories of the rat PFC.

Sex-dependent effects of in utero cannabinoid exposure on cortical function.

Cannabinoids can cross the placenta, thus may interfere with fetal endocannabinoid signaling during neurodevelopment, causing long-lasting deficits. Despite increasing reports of cannabis consumption during pregnancy, the protracted consequences of prenatal cannabinoid exposure (PCE) remain incompletely understood. Here, we report sex-specific differences in behavioral and neuronal deficits in the adult progeny of rat dams exposed to low doses of cannabinoids during gestation. In males, PCE reduced social interaction, ablated endocannabinoid long-term depression (LTD) and heightened excitability of prefrontal cortex pyramidal neurons, while females were spared. Group 1 mGluR and endocannabinoid signaling regulate emotional behavior and synaptic plasticity. Notably, sex-differences following PCE included levels of mGluR1/5 and TRPV1R mRNA. Finally, positive allosteric modulation of mGlu5 and enhancement of anandamide levels restored LTD and social interaction in PCE adult males. Together, these results highlight marked sexual differences in the effects of PCE and introduce strategies for reversing detrimental effects of PCE.

Endocannabinoids Mediate Muscarinic Acetylcholine Receptor-Dependent Long-Term Depression in the Adult Medial Prefrontal Cortex.

Cholinergic inputs into the prefrontal cortex (PFC) are associated with attention and cognition; however there is evidence that acetylcholine also has a role in PFC dependent learning and memory. Muscarinic acetylcholine receptors (mAChR) in the PFC can induce synaptic plasticity, but the underlying mechanisms remain either opaque or unresolved. We have characterized a form of mAChR mediated long-term depression (LTD) at glutamatergic synapses of layer 5 principal neurons in the adult medial PFC. This mAChR LTD is induced with the mAChR agonist carbachol and inhibited by selective M1 mAChR antagonists. In contrast to other cortical regions, we find that this M1 mAChR mediated LTD is coupled to endogenous cannabinoid (eCB) signaling. Inhibition of the principal eCB CB1 receptor blocked carbachol induced LTD in both rats and mice. Furthermore, when challenged with a sub-threshold carbachol application, LTD was induced in slices pretreated with the monoacylglycerol lipase (MAGL) inhibitor JZL184, suggesting that the eCB 2-arachidonylglyerol (2-AG) mediates M1 mAChR LTD. Yet, when endogenous acetylcholine was released from local cholinergic afferents in the PFC using optogenetics, it failed to trigger eCB-LTD. However coupling patterned optical and electrical stimulation to generate local synaptic signaling allowed the reliable induction of LTD. The light-electrical pairing induced LTD was M1 mAChR and CB1 receptor mediated. This shows for the first time that connecting excitatory synaptic activity with coincident endogenously released acetylcholine controls synaptic gain via eCB signaling. Together these results shed new light on the mechanisms of synaptic plasticity in the adult PFC and expand on the actions of endogenous cholinergic signaling.