Autism spectrum disorder is a neurodevelopmental syndrome diagnosed primarily by persistent deficits in social interactions and communication, unusual sensory reactivity, motor stereotypies, repetitive behaviors, and restricted interests. No FDA‐approved medical treatments exist for the diagnostic symptoms of autism. Here we interrogate multiple pharmacological targets in two distinct mouse models that incorporate well‐replicated autism‐relevant behavioral phenotypes. Compounds that modify inhibitory or excitatory neurotransmission were selected to address hypotheses based on previously published biological abnormalities in each model. Shank3B is a genetic model of a mutation found in autism and Phelan‐McDermid syndrome, in which deficits in excitatory neurotransmission and synaptic plasticity have been reported. BTBR is an inbred strain model of forms of idiopathic autism in which reduced inhibitory neurotransmission and excessive mTOR signaling have been reported. The GABA‐A receptor agonist gaboxadol significantly reduced repetitive self‐grooming in three independent cohorts of BTBR. The TrkB receptor agonist 7,8‐DHF improved spatial learning in Shank3B mice, and reversed aspects of social deficits in BTBR. CX546, a positive allosteric modulator of the glutamatergic AMPA receptor, and d‐cycloserine, a partial agonist of the glycine site on the glutamatergic NMDA receptor, did not rescue aberrant behaviors in Shank3B mice. The mTOR inhibitor rapamycin did not ameliorate social deficits or repetitive behavior in BTBR mice. Comparison of positive and negative pharmacological outcomes, on multiple phenotypes, evaluated for replicability across independent cohorts, enhances the translational value of mouse models of autism for therapeutic discovery. GABA agonists present opportunities for personalized interventions to treat components of autism spectrum disorder. Autism Res 2019, 12: 401–421 © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. Lay Summary Many of the risk genes for autism impair synapses, the connections between nerve cells in the brain. A drug that reverses the synaptic effects of a mutation could offer a precision therapy. Combining pharmacological and behavioral therapies could reduce symptoms and improve the quality of life for people with autism. Here we report reductions in repetitive behavior by a GABA‐A receptor agonist, gaboxadol, and improvements in social and cognitive behaviors by a TrkB receptor agonist, in mouse models of autism.

Oxytocin (OT) elicits weight loss in diet-induced obese (DIO) rodents, nonhuman primates and humans by reducing food intake and increasing energy expenditure. In addition to being important in the regulation of energy balance, OT is involved in social behaviors including parent-infant bonds, friendships, and pair bonds. However, the impact of social context on susceptibility to diet-induced obesity (DIO) and feeding behavior (including food sharing) has not been investigated in a rodent model that forms strong social bonds (i.e. prairie vole). Our goals were to determine in Prairie voles (Microtus ochrogaster) whether i) social context impacts susceptibility to DIO and ii) chronic intranasal OT reverses DIO. Voles were housed in divided cages with holes in the divider and paired with a same-sex animal with either the same food [high fat diet (HFD)/HFD, [low fat diet (LFD; chow)/chow], or the opposite food (HFD/chow or chow/HFD) for 19 weeks. HFD-fed voles pair-housed with voles maintained on the HFD demonstrated increased weight relative to pair-housed voles that were both maintained on chow. The study was repeated to determine the impact of social context on DIO susceptibility and body composition when animals are maintained on purified sugar-sweetened HFD and LFD to enhance palatability. As before, we found that voles demonstrated higher weight gain on the HFD/HFD housing paradigm, in part, through increased energy intake and the weight gain was a consequence of an increase in fat mass. However, HFD-fed animals housed with LFD-fed animals (and vice versa) showed intermediate patterns of weight gain and evidence of food sharing. Of translational importance is the finding that chronic intranasal OT appeared to reduce weight gain in DIO voles through a decrease in fat mass with no reduction in lean body mass. These effects were associated with transient reductions in food intake and increased food sharing. These findings identify a role of social context in the pathogenesis of DIO and indicate that chronic intranasal OT treatment reduces weight gain and body fat mass in DIO prairie voles, in part, by reducing food intake.