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.

Effect of the social environment on olfaction and social skills in WT and a mouse model of autism

“…Chronic social isolation in Nlgn3 R451C KI males increased social interaction with females and normalized male aggression phenotype towards females, along with female urine exploration to WT levels 46 . The CX3CR1 receptor, implicated in ASD 11 , exhibits increased protein levels due to social isolation in the prefrontal cortex, nucleus accumbens and hippocampus 47 . Chronic isolation reduced prepulse inhibition only in WT and increased traveled distance in both WT and Cx3cr1 KO male mice 47 .…”

“…However, they have limited e cacies and come with side effects. Numerous compounds targeting receptors or signaling pathways have been extensively tested 11 , but they have failed in clinical trials. Their lack of e cacy can be attributed to the large placebo effect observed in ASD and the inherent diversity among patients.…”

“…Their lack of e cacy can be attributed to the large placebo effect observed in ASD and the inherent diversity among patients. Treatment options hinge on the development of chemical and biochemical compounds that target G protein coupled receptors, highly tunable proteins that control dysregulated signaling pathways in ASD 11 . These receptors hold promise for developing new therapeutic treatments in subtypes of ASD patients.…”

Effect of Schizophrenia linkedDRD2gene mutations and correlation of social behavior with biochemical changes in a post-weaning isolated mouse model

“…Hyperactivity of dopamine in the mesolimbic pathway in the subcortical region augments D (2) dopamine receptor activation and mediates positive psychotic symptoms of Schizophrenia, where the manifestation of the illness is divided into positive (delusions, hallucinations, thought disorganisation, paranoia) or negative (lack of drive and motivation, alogia, social withdrawal) symptoms, with cognitive impairments. The negative symptoms and cognitive decline are thought to arise from reduced D(1) dopamine receptor stimulation (Shen et al, 2012;Brisch et al, 2014).…”

“…Studying the physiological functions and mechanisms facilitated by the interactions between the unmutated proteins, and the impact of mutations on these protein interactions aid us in determining the mechanism of disorder manifestation (Rao et al, 2014;Bugge et al, 2020).Our in silico analysis in the current study demonstrates the effect of the mutations in different genes related to neurological conditions on their encoded protein structures and predicted the possible alteration in synaptic signaling, specifically the DRD2. In addition to its schizophrenia association, DRD2 is one of the strongest candidates linked to ASD, and targeting its activity might be a potential therapeutic strategy (Annamneedi et al, 2023). Further studies are required to address the altered interaction between Neuronal calcium sensor 1 and D(2) dopamine receptor, due to the mutation and its relevance to both schizophrenia and ASD and in developing the common therapeutic strategies.…”