Inhibition of TRPV4 rescues circuit and social deficits unmasked by acute inflammatory response in a Shank3 mouse model of Autism

Abstract

Autism spectrum disorder is a neurodevelopmental disease characterized by social deficits and repetitive behaviors. The high heterogeneity of the disease may be explained by gene and environmental interactions and potential risk factors include immune dysfunctions and immune-mediated co-morbidities. Mutations in the SHANK3 gene have been recognized as a genetic risk factor for ASD. While heterozygous SHANK3 mutations are usually the types of mutations associated with idiopathic autism in patients, heterozygous deletion of Shank3 gene in mice does not commonly induce ASD-related behavioural deficit. Here, we used in-vivo and ex-vivo approaches to demonstrate that region-specific neonatal downregulation of Shank3 in the NAc promotes D1R-MSN hyperexcitability and upregulates Trpv4 to impair social behaviour. Interestingly, genetically vulnerable Shank3+/- mice, when challenged with Lipopolysaccharide to induce inflammatory response, showed similar circuit and behavioural alterations that were rescued by acute Trpv4 inhibition. Altogether our data demonstrate shared molecular and circuit mechanisms between ASD-relevant genetic alterations and environmental insults, which ultimately lead to sociability dysfunctions.

Balance between direct and indirect pathways of the nucleus accumbens controls social behavior in mice

“…These findings are consistent with a prosocial role of D1R-SPNs in the NAc, in agreement with their activation (VTAprojecting D1R-SPNs) during social encounter (48) and the effects of their optogenetic stimulation in typically behaving (13,54) or depressive-like (32) mice. In contrast, Shank3 knockdown in NAc D1R-SPN increased their excitability and concomitantly reduced social preference in mice (54), suggesting that excessive D1R-SPN activity may also lead to social avoidance, possibly by involving VP-projecting populations (48). However, increased D1R-SPN excitability in Shank3 mutant mice can co-exist with decreased output activity, as seen in mouse models of depression (32).…”

“…The primary focus of ablation experiments being the D1R-SPNs of the NAc, we used D1R-SPN ablation in the DS and D2R-SPN ablation in the NAc as controls, but we did not explore the role of D2R-SPNs in the DS. Similarly, in optogenetic studies, we did not assess the consequences of prolonged D1R-SPN stimulation of social behavior, which may result in social aversion (48, 54) as well as D2R-SPN stimulation. Further studies will be required to further investigate the consequences of D2R-SPN ablation in the DS and D1R-SPN stimulation in the NAc.…”

“…Indirect evidence argues for similar opposing roles of D1R-SPNs and D2R-SPNs in modulating social behavior. Optogenetic stimulation of NAc D1R-SPNs in typically behaving mice increases social approach (13, 54); social encounter with a female mouse activates VTA-projecting D1R-SPNs in the NAc of male mice (48). In the chronic social defeat stress (SDS) model of depression, social avoidance strongly correlated with D2R-SPN excitability and stimulating these neurons in the NAc of naïve mice produced social avoidance following subthreshold SDS.…”

“…Suppressing endocannabinoid 2-arachidonoylglycerol (2-AG) signaling in D1R-SPNs also blunted sociability, an effect mimicked by local ablation in the DS (57). Finally, knocking down the Shank3 gene in NAc D1R-SPNs impaired social preference (54). Together, these studies point to D1R-SPNs, notably in the NAc, as driving pro-social behavior, whereas activation of D2R-SPNs would rather promote social avoidance.…”

Genetic ablation of metabotropic glutamate receptor 5 in rats results in an autism-like behavioral phenotype

“…Although the exact etiology of ASD remains an enigma, at least 30% of cases have an underlying genetic etiology [28][29][30][31][32][33][34][35]. The most common gene variants involved in ASD include SHANK3, MECP2, NLGN3, NRXN1 and FMR1 [36][37][38][39][40][41][42][43][44][45][46][47][48][49][50], some of which are regulated by the metabotropic glutamate receptor (mGluR) pathway, especially mGluR5, thus making it a very attractive target for understanding the pathogenesis of ASD [51]. mGluR5 is a seven-transmembrane spanning G-protein coupled receptor (GPCR) located in the postsynaptic membrane of excitatory synapses, neuronal nuclear membranes, glia, and oligodendrocytes [52][53][54][55][56].…”