Towards the convergent therapeutic potential of GPCRs in autism spectrum
disorders
Abstract
Autism spectrum disorders (ASD) are diagnosed in 1/100 childbirth
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
mediate the transfer of extracellular signals to convergent
intracellular signalling and downstream cellular responses that are
dysregulated in ASD. Despite hundreds of GPCRs are expressed in the
brain, only 23 GPCRs are genetically associated to ASD according to the
Simons Foundation Autism Research Initiative (SFARI) gene database:
oxytocin OTR, vasopressin V1A, V1B, metabotropic glutamate mGlu5, mGlu7,
GABAB, dopamine D1, D2, D3, serotoninergic 5-HT1B, β2-adrenoceptor,
cholinergic M3, adenosine A2A, A3, angiotensin AT2, cannabinoid CB1,
chemokine CX3CR1, orphan GPR37, GPR85 and olfactory OR1C1, OR2M4,
OR2T10, OR52M1. Here, we review the therapeutical potential of these 23
GPCRs, in addition to 5-HT2A, 5-HT6 and 5-HT7 for their relevance to
ASD. We discuss their genetic association with ASD, the effects of their
genetic and pharmacological manipulation in animal models and humans,
their existing pharmacopeia towards core symptoms of ASD and rank them
based on these evidences. Among these 23 GPCRs, we highlight that OTR,
V1A, mGlu5, D2, 5-HT2A, CB1, and GPR37 are the best therapeutic targets.
We conclude that the dysregulation of GPCRs and their signalling is a
convergent pathological mechanism of ASD and their therapeutic potential
has only begun as multiple GPCRs could mitigate ASD.