Role of type 1 cannabinoid receptors in synaptic and behavioural alterations associated to experimental model of multiple sclerosis

Cannabinoid receptors type 1 (CB1R) are important regulators of the neurodegenerative damage in multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis (EAE). In GABAergic striatal neurons, CB1R stimulation exerts protective effects by limiting inflammation-induced potentiation of glutamate-mediated spontaneous excitatory postsynaptic currents (sEPSCs). Mood disorders, including anxiety and depression, are frequently diagnosed in MS patients, even independently of the disabling symptoms associated with the disease. Anatomical, biochemical, and pharmacological evidence indicates that CB1Rs is implicated in the control of emotional behaviour, and are modulated during inflammatory neurodegenerative diseases such as MS and experimental autoimmune encephalomyelitis (EAE). We aimed to study further the role of CB1Rs in the EAE-associated synaptopathy and to address the possible role of CB1R in anxiety-like behaviour in mice with EAE by performing behavioural and electrophysiological experiments. Here we show that CB1Rs 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 CB1R on GABAergic neurons (GABA-CB1R-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 CB1R on glutamatergic neurons (Glu-CB1R-KO), indicating that this subset of receptors controls the effects of inflammation on glutamate release. While EAE severity has been shown enhanced in whole CB1R-KO mice, GABA-CB1R-KO and Glu-CB1R-KO mice had similar motor deficits as the respective wild-type (WT) counterparts. EAE-induced behavioural alterations downregulated CB1R mediated control over striatal synaptic transmission, and were exacerbated in mice lacking CB1R (CB1R-KO mice). Even prior to the appearance of motor deficits, central blockade of interleukin-1β (IL-1β) reversed the anxiety-like phenotype of EAE mice. Our results provide additional evidence that CB1Rs 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. We showed that CB1Rs are critically involved in EAE-related anxiety, and establish a previously unrecognized link between mood alterations and IL-1β-dependent inflammatory neurodegeneration in EAE and, possibly, MS.