Towards the convergent therapeutic potential of GPCRs in autism spectrum disorders

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

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Towards the convergent therapeutic potential of G protein‐coupled receptors in autism spectrum disorders

International audienceAutism spectrum disorders (ASDs) 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 cellsurface 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 and V 1B ; metabotropic glutamate mGlu 5 and mGlu 7 ; GABA B2 ; dopamine D 1 , D 2 and D 3 ; serotoninergic 5-HT 1B ; β 2-adrenoceptor; cholinergic M 3 ; adenosine A 2A and A 3 ; angiotensin AT 2 ; cannabinoid CB 1 ; chemokine CX 3 CR1; orphan GPR37 and GPR85; and olfactory OR1C1, OR2M4, OR2T10 and OR52M1. Here, we review the therapeutic potential of these 23 GPCRs, as well as 5-HT 2A and 5-HT 7 , for ASD. For each GPCR, we discuss its genetic association, genetic and pharmacological manipulation in animal models, pharmacopoeia for core symptoms of ASD and rank them based on these factors. Among these GPCRs, we highlight D 2 , 5-HT 2A , CB 1 , OTR and V 1A as the more 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

Towards the convergent therapeutic potential of GPCRs in autism spectrum disorders

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 (β2) 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

Effect of the social environment on olfaction and social skills in WT and mouse model of autism: Social isolation normalizes Shank3 knockout phenotype

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

Effect of the social environment on olfaction and social skills in WT and mouse model of autism: Social isolation normalizes Shank3 knockout phenotype

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

Effect of the social environment on olfaction and social skills in WT and mouse model of autism: Social isolation normalizes Shank3 knockout phenotype

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

Effect of the social environment on olfaction and social skills in WT and mouse model of autism: Social isolation normalizes Shank3 knockout phenotype

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