Abstract
Mutations in the SHANK3 gene have been recognized as a genetic risk factor for Autism Spectrum Disorder (ASD), a neurodevelopmental disease characterized by social deficits and repetitive behaviors. 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 behavioral deficit. Here, we used in-vivo and ex-vivo approaches to demonstrate that region-specific neonatal downregulation of Shank3 in the Nucleus Accumbens promotes D1R-medium spiny neurons (D1R-MSNs) hyperexcitability and upregulates Transient Receptor Potential Vanilloid 4 (Trpv4) to impair social behavior. Interestingly, genetically vulnerable Shank3+/− mice, when challenged with Lipopolysaccharide to induce an acute inflammatory response, showed similar circuit and behavioral 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.
Highlights
Autism spectrum disorder (ASD) includes a heterogeneous group of neurodevelopmental diseases characterized by social communication deficits and repetitive behaviors
Mutations in SHANK3 gene, coding for a scaffolding protein located at excitatory synapses, account for 1−2% of all ASD cases, and its haploinsufficiency is acknowledged to lead to a high-penetrance form of ASD, known as Phelan-McDermid syndrome (PMS) [1, 2]
Social deficits following early Nucleus Accumbens (NAc)-specific Shank3 insufficiency Given the emerging importance of NAc in social reward processing [9, 25], we first focused our investigation on this brain circuit and asked whether Shank3 downregulation restricted to this region would lead to sociability deficits
Summary
Autism spectrum disorder (ASD) includes a heterogeneous group of neurodevelopmental diseases characterized by social communication deficits and repetitive behaviors. The development of pharmacological interventions to alleviate ASD-related sociability symptoms is limited by several factors, including the relative lack of understanding of the genetic consequences of SHANK3 insufficiency. This is further complicated by the fact that Shank plays specific roles depending on its expression pattern in different regions and cell types [3]. Despite the fact that neuronal deficits within the reward system have been revealed in different Shank animal models [13, 14] and that expression of Shank in the striatum is enriched [15], the contribution of Shank insufficiency in the ventral striatum, which includes the NAc, to ASD symptomatology has been largely neglected
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