Activation of the medial preoptic area (MPOA) ameliorates loss of maternal behavior in a Shank2 mouse model for autism

Impairments in social relationships and awareness are features observed in autism spectrum disorders (ASDs). However, the underlying mechanisms remain poorly understood. Shank2 is a high‐confidence ASD candidate gene and localizes primarily to postsynaptic densities (PSDs) of excitatory synapses in the central nervous system (CNS). We show here that loss of Shank2 in mice leads to a lack of social attachment and bonding behavior towards pubs independent of hormonal, cognitive, or sensitive deficits. Shank2 −/− mice display functional changes in nuclei of the social attachment circuit that were most prominent in the medial preoptic area (MPOA) of the hypothalamus. Selective enhancement of MPOA activity by DREADD technology re‐established social bonding behavior in Shank2 −/− mice, providing evidence that the identified circuit might be crucial for explaining how social deficits in ASD can arise. Synopsis Loss of the autism spectrum disorder linked gene Shank2 in mice leads to lack of social bonding due to functional changes in the social attachment neurocircuitry. Shank2 −/− mice are unable to initiate social bonding towards pups. Shank2 −/− mice show impaired glutamatergic signaling in the brain circuit social attachment circuit including the the medial preoptic area (MPOA) of the hypothalamus. The behavioral alterations seem to be independent of hormonal influences, and cognitive and sensory deficits. Chemogenetic activation of MPOA neurons rescues the loss of social bonding in Shank2 −/− mice. Graphical Abstract Loss of the autism spectrum disorders linked gene Shank2 in mice leads to loss of social bonding due to functional changes in the social attachment circuit including the MPOA.