Towards the convergent therapeutic potential of GPCRs in autism spectrum disorders.

Autism spectrum disorders (ASD) are diagnosed in 1/100 children worldwide, based on two core symptoms, deficits in social interaction and communication and stereotyped behaviours. G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors that transduce extracellular signals to convergent intracellular signalling and downstream cellular responses that are commonly dysregulated in ASD. Despite hundreds of GPCRs being expressed in the brain, only 23 are genetically associated with ASD according to the Simons Foundation Autism Research Initiative (SFARI) gene database: oxytocin OTR, vasopressin V 1A , V 1B , metabotropic glutamate mGlu 5 , mGlu 7 , GABA B2 , dopamine D 1 , D 2 , D 3 , serotoninergic 5-HT 1B , β 2 -adrenoceptor, cholinergic M 3 , adenosine A 2A , A 3 , angiotensin AT 2 , cannabinoid CB 1 , chemokine CX 3 CR1, orphan GPR37, GPR85 and olfactory OR1C1, OR2M4, OR2T10, OR52M1. Here, we review the therapeutic potential of these 23 GPCRs, 5-HT 2A and 5-HT 7 for ASD. For each GPCR, we discuss its genetic association, genetic and pharmacological manipulation in animal models, pharmacopeia for core symptoms of ASD and rank them based on these factors. Among these GPCRs, we highlight that D 2 , 5-HT 2A , CB 1 , OTR and V 1A are the most promising targets for ASD. We discuss that the dysregulation of GPCRs and their signalling is a convergent pathological mechanism of ASD. Their therapeutic potential has only begun as multiple GPCRs could mitigate ASD.