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Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impairments in social interaction, communication, as well as restrained or stereotyped behaviors. The inherent heterogeneity within the autism spectrum poses challenges for developing effective pharmacological treatments targeting core features. Successful clinical trials require the identification of robust markers to enable patient stratification. In this study, we explored molecular markers within the oxytocin and immediate early gene families across five interconnected brain structures of the social circuit in four distinct ASD mouse models, each exhibiting unique behavioral features along the autism spectrum. While dysregulations in the oxytocin family were model-specific, immediate early genes displayed widespread alterations, reflecting global changes in social plasticity. Through integrative analysis, we identified Egr1, Foxp1, Homer1a, Oxt and Oxtr as five robust and discriminant molecular markers facilitating successful stratification of the four models. Importantly, our stratification demonstrated predictive values when challenged with a fifth mouse model or identifying subgroups of mice potentially responsive to oxytocin treatment. Beyond providing insights into oxytocin and immediate early gene mRNA dynamics, this proof-of-concept study represents a significant step toward potential stratification of individuals with ASD. The implications extend to enhancing the success of clinical trials and guiding personalized medicine for distinct subgroups of individuals with autism.

Autism spectrum disorders are complex, polygenic and heterogenous neurodevelopmental conditions, imposing a substantial economic burden. Genetics are influenced by the environment, specifically the social experience during the critical neurodevelopmental period. Despite efficacy of early behavior interventions targeted specific behaviors in some autistic children, there is no sustainable treatment for the two core symptoms: deficits in social interaction and communication, and stereotyped or restrained behaviors or interests. In this study, we investigated the impact of the social environment on both wild-type (WT) and Shank3 knockout (KO) mice, a mouse model that reproduces core autism-like symptoms. Our findings revealed that WT mice raised in an enriched social environment maintained social interest towards new conspecifics across multiple trials. Additionally, we observed that 2 hours or chronic social isolation induced social deficits or enhanced social interaction and olfactory neuron responses in WT animals, respectively. Notably, chronic social isolation restored both social novelty and olfactory deficits, and normalized self-grooming behavior in Shank3 KO mice. These results novel insights for the implementation of behavioral intervention and inclusive classrooms programs for children with ASD.

Changes in genetic and/or environmental factors to developing neural circuits and subsequent synaptic functions are known to be a causative underlying the varied socio-emotional behavioural patterns associated with autism spectrum disorders (ASD). Seven transmembrane G protein-coupled receptors (GPCRs) comprising the largest family of cell-surface receptors, mediate the transfer of extracellular signals to downstream cellular responses. Disruption of GPCR and their signalling have been implicated as a convergent pathologic mechanism of ASD. Here, we aim to review the literature about the 23 GPCRs that are genetically associated to ASD pathology according to Simons Foundation Autism Research Initiative (SFARI) database such as oxytocin (OXTR) and vasopressin (V1A, V1B) receptors, metabotropic glutamate (mGlu5, mGlu7) and gamma-aminobutyric acid (GABAB) receptors, dopamine (D1, D2), serotoninergic (5-HT1B and additionally included the 5-HT2A, 5-HT7 receptors for their strong relevance to ASD), adrenergic ($\beta$2) and cholinergic (M3) receptors, adenosine (A2A, A3) receptors, angiotensin (AT2) receptors, cannabinoid (CB1) receptors, chemokine (CX3CR1) receptors, orphan (GPR37, GPR85) and olfactory (OR1C1, OR2M4, OR2T10, OR52M1) receptors. We discussed the genetic variants, relation to core ASD behavioural deficits and update on pharmacological compounds targeting these 23 GPCRs. Of these OTR, V1A, mGlu5, D2, 5-HT2A, CB1, and GPR37 serve as the best therapeutic targets and have potential towards core domains of ASD pathology. With a functional crosstalk between different GPCRs and converging pharmacological responses, there is an urge to develop novel therapeutic strategies based on multiple GPCRs to reduce the socioeconomic burden associated with ASD and we strongly emphasize the need to prioritize the increased clinical trials targeting the multiple GPCRs.