Sex bias in social deficits, neural circuits and nutrient demand in Cttnbp2 autism models.

Researchers studied mice with autism-like traits to understand why autism affects more boys than girls. They found male mice had social problems while female mice were mostly protected. The brain activity and protein patterns were different between males and females. Importantly, giving male mice extra amino acids and zinc improved their social behaviors, suggesting nutrition might play a role in autism's male bias.

This preclinical study investigated sex differences in autism using Cttnbp2 mutant mice, a model of autism spectrum disorder. Researchers found that male mice exhibited social deficits while females were largely protected. Seven brain regions, including the infralimbic cortex, showed reduced activity in males during social interactions. Proteomic analysis revealed sex-specific molecular differences, with males showing downregulated synaptic proteins and females showing upregulated mTOR-related proteins.

Notably, supplementation with branched-chain amino acids (BCAA) activated the mTOR pathway and rescued social behaviors in male mice. Males also required increased zinc intake for normal social functioning. These findings suggest differential nutritional demands may contribute to autism's male bias and point toward potential therapeutic targets.

Findings suggest sex-specific nutritional interventions, particularly BCAA and zinc supplementation, may benefit males with autism. Results support investigating metabolic differences between sexes in autism and considering personalized nutritional approaches based on biological sex.

Study conducted in mouse models may not directly translate to humans. Sample sizes not reported. Single gene mutation model may not represent broader autism spectrum. Mechanism of female protection requires further investigation.

Autism spectrum disorders caused by both genetic and environmental factors are strongly male-biased neuropsychiatric conditions. However, the mechanism underlying the sex bias of autism spectrum disorders remains elusive. Here, we use a mouse model in which the autism-linked gene Cttnbp2 is mutated to explore the potential mechanism underlying the autism sex bias. Autism-like features of Cttnbp2 mutant mice were assessed via behavioural assays.

C-FOS staining identified sex-biased brain regions critical to social interaction, with their roles and connectivity then validated by chemogenetic manipulation. Proteomic and bioinformatic analyses established sex-biased molecular deficits at synapses, prompting our hypothesis that male-biased nutrient demand magnifies Cttnbp2 deficiency. Accordingly, intakes of branched-chain amino acids (BCAA) and zinc were experimentally altered to assess their effect on autism-like behaviours. Both deletion and autism-linked mutation of Cttnbp2 result in male-biased social deficits.

Seven brain regions, including the infralimbic area of the medial prefrontal cortex (ILA), exhibit reduced neural activity in male mutant mice but not in females upon social stimulation. ILA activation by chemogenetic manipulation is sufficient to activate four of those brain regions susceptible to Cttnbp2 deficiency and consequently to ameliorate social deficits in male mice, implying an ILA-regulated neural circuit is critical to male-biased social deficits. Proteomics analysis reveals male-specific downregulated proteins (including SHANK2 and PSD-95, two synaptic zinc-binding proteins) and female-specific upregulated proteins (including RRAGC) linked to neuropsychiatric disorders, which are likely relevant to male-biased deficits and a female protective effect observed in Cttnbp2 mutant mice. Notably, RRAGC is an upstream regulator of mTOR that senses BCAA, suggesting that mTOR exerts a beneficial effect on females.

Indeed, increased BCAA intake activates the mTOR pathway and rescues neuronal responses and social behaviours of male Cttnbp2 mutant mice. Moreover, mutant males exhibit greatly increased zinc demand to display normal social behaviours. Mice carrying an autism-linked Cttnbp2 mutation exhibit male-biased social deficits linked to specific brain regions, differential synaptic proteomes and higher demand for BCAA and zinc. We postulate that lower demand for zinc and BCAA are relevant to the female protective effect.

Our study reveals a mechanism underlying sex-biased social defects and also suggests a potential therapeutic approach for autism spectrum disorders.