Pre- and postsynaptic type-1 cannabinoid receptors control the alterations of glutamate transmission in experimental autoimmune encephalomyelitis.

Abstract Type-1 cannabinoid receptors (CB 1 R) are important regulators of the neurodegenerative damage in multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis (EAE). In GABAergic striatal neurons, CB 1 R stimulation exerts protective effects by limiting inflammation-induced potentiation of glutamate-mediated spontaneous excitatory postsynaptic currents (sEPSCs). Here we show that CB 1 R located on GABAergic or on glutamatergic neurons are differentially involved in the pre- and postsynaptic alterations of sEPSCs caused by EAE in the striatum. After induction of EAE, mice selectively lacking CB 1 R on GABAergic neurons (GABA-CB 1 R-KO) showed exacerbated alterations of sEPSC duration in GABAergic medium spiny neurons (MSN). On the other hand, EAE-induced alterations of corticostriatal sEPSC frequency were exacerbated only in mice lacking CB 1 R on glutamatergic neurons (Glu-CB 1 R-KO), indicating that this subset of receptors controls the effects of inflammation on glutamate release. While EAE severity was enhanced in whole CB 1 R-KO mice, GABA-CB 1 R-KO and Glu-CB 1 R-KO mice had similar motor deficits as the respective wild-type (WT) counterparts. Our results provide further evidence that CB 1 R are involved in EAE pathophysiology, and suggest that both pre- and postsynaptic alterations of glutamate transmission are important to drive excitotoxic neurodegeneration typical of this disorder.