Towards the convergent therapeutic potential of GPCR s in autism spectrum disorders Anil ANNAMNEEDI12 Caroline GORA1 Ana DUDAS1 Xavier LERAY1 Véronique BOZON1

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Towards the convergent therapeutic potential of GPCRs in autism spectrum

disorders

Anil ANNAMNEEDI1,2#, Caroline GORA1, Ana DUDAS1, Xavier LERAY1, Véronique BOZON1,

Pascale CREPIEUX1, Lucie P. PELLISSIER1#

1 Team biology of GPCR Signaling systems (BIOS), CNRS, IFCE, INRAE, Université de Tours, PRC, F-37380, Nouzilly,

France.

2 LE STUDIUM Loire Valley Institute for Advanced Studies, 45000, Orléans, France.

# Corresponding authors:

Anil ANNAMNEEDI, PhD. Email: anil.annamneedi@inrae.fr; orcid.org/0000-0002-6743-8627

Lucie P. PELLISSIER, PhD. Email: lucie.pellissier@inrae.fr; orcid.org/0000-0001-7085-3242

Keywords

G protein coupled receptor, autism spectrum disorder, social interaction, signalling pathway,

neurotransmitter

ABSTRACT

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 socio-economic burden associated with ASD and we strongly

emphasize the need to prioritize the increased clinical trials targeting the multiple GPCRs.

INTRODUCTION

Autism spectrum disorder (ASD) is a neurodevelopmental disorder diagnosed on core clinical

symptoms defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition

(DSM-V), social interaction and communication deficits and stereotyped, restrained or

compulsive behaviours. ASD often associates with comorbid symptoms, such as anxiety,

epilepsy, sleep disturbances, motor coordination impairment, gastro-intestinal disorders,

intellectual disability. Whereas its worldwide prevalence is around 1/100 child birth, its

aetiology remains not fully understood as 70% of cases remains sporadic, highlighting the

polygenic complexity of the disease. Currently, there is no pharmacological drug treatment

for the core symptoms of autism. Clinical trials did not lead to successful outcome due to

important placebo effect, lack of efficacy and potentially the large aetiological diversity of

patients. Therefore, two main gaps remain in autism research: the identification of convergent

and robust therapeutical targets and the development of potent drugs to succeed in clinical

trials probably only in sub-class of patients, determined based on the complex multigenic

profile, to achieve successful clinical trials. New advances need to overcome these challenges.

Important recent sequencing studies in large ASD cohorts robustly identified hundreds of de

novo candidate genes that converge in two main categories ‘gene expression regulation’ or

‘neuronal communication, signalling or plasticity’ [1-3]. These genes are mostly expressed in

developing excitatory and inhibitory cortical neurons of the human cortex [1]. Rather than a

single mutation, accumulation of risk alleles and increase or decrease copy number variants

may underly the pathological process among affected individuals [4]. More than a thousand

of candidate genes are listed in the Simons Foundation Autism Research Initiative (SFARI)

database (https://gene.sfari.org). Currently, one of the main research areas in ASD is to

transform the large number of identified candidate and risk alleles in convergent

neurobiological mechanism [4]. Genomic and transcriptomic data from patients converge to

identify common intracellular signalling pathways, with enriched Wnt/β-catenin or Notch

signalling in early embryonic development cluster and ERK, AKT, mTOR or Wnt/β-catenin

signalling in postnatal development cluster [2, 3, 5].

Interestingly, G protein-coupled receptors (GPCRs) are key master regulators of these

intracellular pathways, neuronal communication and plasticity and gene expression. In fact,

numerous genes identified in ASD meta-analysis modules are either their

neurotransmitter/ligands (Wnt), GPCRs themselves (5-HT2A), their direct effectors (Protein

Kinase C), scaffolding partners (SHANK), downstream signalling pathways (ERK), or

transcription factors (the cAMP response element binding protein CREB) [3]. In this review,

we focus on the convergent potential of GPCRs in ASD and why this receptor family fulfil all

criteria of promising therapeutical targets for ASD. Based their fine tune pharmacology and

their diversity, GPCRs represent the greatest therapeutical options for ASD to lead successful

clinical trials. Here, we will describe all the GPCR pathogenic (copy number, loss of function,

missense, frameshift, stop gained) variants associated to ASD so far, but also emphasize that

they are the most dysregulated genes in ASD, they are fine tune targets with innovative

pharmaceutical agents and they control multiple signalling and biological processes that are

convergent in this neurodevelopmental disorder.

1) GPCRs receptor family are therapeutical targets for ASD

Canonical GPCRs display seven transmembrane (TM) helices and an extracellular domain

composed of the N-terminus and three extracellular loops 1-3 (EL1-3) involved in ligand

binding, conformational changes and activation transmission to the intracellular signalling

domain (Figure 1). The intracellular domain, composed of the three intracellular loops 1-3

(IL1-3) and the C-terminus with an 8th helix parallel to the plasma membrane, induces

intracellular signalling molecular recruitment and activation (e.g., heterotrimeric G protein

and -arrestin). Whereas their versatile nature was a major issue for a long time, many GPCR

structures in inactive, intermediate and active conformations are now available with the

development of cryo-microscopy. GPCRs are translated inside the membrane of the

endoplasmic reticulum (ER), thus actively exported to the plasma membrane. Due to their

molecular complexity, they are often prone to misfolding or lack of ER export, which may

result in cell toxicity [6]. Most of GPCRs, splicing isoforms and their signalling molecules are

expressed in the Central Nervous System (CNS) [7, 8], located at the plasma membrane of

soma, dendrites and/or axons (in pre-, post- and/or peri-synaptic compartments) of neurons,

but also in astrocytes, oligodendrocytes and microglia. Some GPCRs display widespread

expression profiles throughout the brain (e.g., glutamate or GABA metabotropic receptors or

GPR85) and others have a discrete and brain structure or cell-type specific pattern (e.g.,

GPR37, GPR88, vasopressin V1B receptor) [9, 10]. Transcriptomic data from prefrontal cortex

tissue showed that GPCRs are more dysregulated compared to other family genes in ASD and

in other neurodevelopmental and psychiatric disorders [11]. At global level, around 200 GPCR

genes have been shown to be potentially linked with autism and among them, 25% were

shown to be dysregulated. Among them, 74% belong to the class A with adenosine ADORA1

and adrenergic ADRA1D being the most down-regulated and 24% are orphan receptors.

Among the downstream signalling partners, the most affected G protein are Gi (also found

in the SFARI gene list) and G12/13 proteins. In 2018, Babu and colleagues’ asses the natural

genetic landscape of GPCRs targeted by a drug in nearly 70 000 individuals from the 1000

genomes project [12] and available in the GPCRdb database [13]. They identified missense or

copy number variants that may influence ligand binding or signalling molecules recruitment.

It included GPCR candidate genes in ASD or their other family members: vasopressin V1B,

dopamine D1, D2, D3 and D5, serotonin 5-HT2A, 5-HT2B, 5-HT2C, 5-HT4 and 1- and 2-adrenergic

and GABAB. This new area of research based on receptor bias is known as pharmacogenomics.

Considering the major impact of GPCR signalling, a slight modification in a GPCR in

combination with another ASD gene variants or GPCRs would lead to a neuronal pathogenic

process. Application of pharmacogenomics remains an outstanding hypothesis to decipher

the processes underlying this neurodevelopmental disorder. Despite these evidences, further

studies are needed to fully understand the convergent role of GPCRs and which GPCR or GPCR-

dependent signalling molecules are involved in ASD aetiology.

- GPCRs display the most diversity of pharmacological agents

GPCRs respond to various ligands ranging from photons, amino acids, peptides up to large

glycosylated proteins (Figure 1A). With around 800 GPCRs, they are the main receptor family

in the CNS and are subdivided into five classes [7]: the largest rhodopsin-like class A, the

secretin/class B, the glutamate/class C, the Frizzled class, the adhesion class. Sensory GPCRs

(e.g., olfactory, vision, taste and pheromone receptors), which accounts for most GPCR genes,

are comprised mostly in class A and few in class C. Although they act as detector of scents in

the olfactory epithelium, the function and expression of olfactory GPCRs in the brain are not

well documented. Till date, hundreds of GPCRs (including olfactory receptors) remains

without any identified ligand and are called orphan receptors.

In addition to their diverse natural ligands, drugs can modulate GPCR activity, with diverse

pharmacological profiles (Figure 1B). Those drugs can either be chemical compounds,

peptides, large autoantibodies and more recently, a new class has appeared, the biologicals

(e.g., antibody fragments) [14], which can be easily encoded and vectorized. Orthosteric

agonists, inverse agonists and antagonists bind in the natural ligand binding pocket and

respectively activate, inactivate the receptor and/or prevent the binding of the endogenous

ligand. In contrast, through binding in allosteric sites, positive or negative allosteric

modulators enhance or decrease the GPCR activity only in presence of its natural ligand.

Finally, GPCRs form cell-specific homo- or hetero-oligomers depending of the GPCR

composition and subcellular localisation in a particular cell type. Each GPCR in the oligomer or

expressed in the same cell may influence the pharmacology of the other GPCRs, opening a

new area of the GPCR pharmacology. Despite their name and classification in subgroups

according to their preferential G protein coupling (e.g., Gs/olf, Gi/o, Gq/11 or G12/13), they

couple to several G proteins. In addition, they recruit -arrestin, leading to specific

intracellular signalling pathways or kinetics, such as ERK kinases and endocytosis. Therefore,

different ligands may favour one coupling over another, which is called signalling bias (Figure

1). This pharmacological property of GPCR is of great interest for therapeutical applications,

as one biased drug can control a wanted signalling cascade, preventing unwanted effects.

Considering oligomerisation status, drug pharmacological profile, receptor or ligand signalling

bias, GPCRs are the most specific and fine-tuned targets.

Figure 1 GPCR signalling and pharmacology

A) GPCR are composed of seven transmembrane domains connecting the extracellular domain (N-terminus,

Extracellular loops (EL) 1-3) where various ligands bind the receptor (e.g., natural ligands and

chemicals/biologicals) to the intracellular domain (Intracellular loops (IL) 1-3, helix H8, C-terminus) that couple

and recruit the direct signalling effectors, which activates the downstream signalling pathways (Akt, ERK) and

cellular processes. A ligand named biased ligand has the particular pharmacological profile to activate one over

the several signalling pathways for a given receptor. Here, we represented a G protein biased ligand that favour

G protein coupling (black two headed arrow) over β-arrestin recruitment (grey two headed arrow). B) GPCRs

display a rich pharmacopeia of ligands, with agonists, antagonists and inverse agonists that bind to the

orthosteric binding site (e.g., the binding site of the natural ligand) to respectively activate, prevent the agonist

binding and inactivate the receptor. In addition, another class of ligand bind allosteric sites that increase or

decrease the efficacy or efficiency of the natural ligand or agonists, respectively called positive or negative

allosteric modulators.

- GPCRs are the most druggable targets for ASD

With 800 genes in the human genome, GPCRs are the most abundant receptor family and

more than half of the GPCRs are expressed in the brain [15, 16]. More than 30% of the drugs

approved on the global market, or in clinical trials, targets a GPCR in various disorders [7, 17,

18]. Nevertheless, 20% of them are used for neurological conditions, including ASD. This small

proportion will increase as hundreds of GPCRs in the CNS remains orphan. Although their

function remains to be fully elucidated, they represent advantageous target in neurological

disorders [10] and especially ASD. So far, no pharmaceutical agent reaches the market to

improve primary symptoms of ASD. The therapeutical potential of GPCRs in ASD has started

with class C mGlu5 and GABAB GPCRs up to phase 2 clinical trials for monogenic Fragile X

syndrome using a negative allosteric modulator and a selective agonist, respectively [19], in

order to restore the glutamate/GABA unbalance. The lack of efficacy of these treatments

might result from the wide expression of these receptors throughout the brain. Since then,

various compounds targeting more discrete GPCRs has been tested. Oxytocin peptide and

vasopressin V1A chemical antagonist administration failed to improve social abilities over

placebo in phase 3 clinical trials whereas vasopressin peptide remains to be tested in larger

cohort of ASD patients [20-22]. Regarding their prosocial effects, the oxytocin/vasopressin

family remains interesting targets for the autism community, but further developments are

needed to overpass placebo effects. Cannabidiol, cannabidivarin or endocannabinoid mix

targeting CB1 receptors passed safety phase 1 clinical trials [23] (https://clinicaltrials.gov/).

Drugs targeting serotonin 5-HT1A and 5-HT2A and dopamine D2 and D3 receptors are approved

in the market for schizophrenia [17]. Considering the ASD-schizophrenia continuum, some of

these drugs could be tested for potential improvement in ASD. Interestingly, the few GPCRs

that have been tested so far are all candidate genes that are listed in the SFARI (Tables 1-2).

Overall, the therapeutical potential of GPCRs has only began to be explored.

- GPCRs are master regulators of intracellular signalling pathway

Upon activation, GPCRs couple to heterotrimeric G protein (,  and  subunits) and recruit -

arrestin. Gs/olf protein activates adenylyl cyclases that hydrolyse ATP in cytoplasmic cAMP

production, which is regulated by phosphodiesterases. cAMP activates exchange protein

activated by cAMP (EPAC), calcium ion channels opening (CNGC) and the protein kinase A

(PKA), which in turn phosphorylates all their downstream effectors (e.g., ERK, PI3K/AKT and

CREB, DARP32, ionotropic glutamatergic receptors). Conversely, Gi/o inhibits adenylyl

cyclases and cAMP production. GNAI1 gene coding Gi1 is a high confidence gene (SFARI gene

list), whereas GNAS, GNB2, ADCY3 and ADCY5 encoding Gs, G and adenylyl cyclase 3 and

5 are strong candidate genes. Gq/11 proteins activate phospholipase C, which hydrolyses

phosphatidylinositol-4,5-bisphosphate into diacylglycerol (DAG) and inositol-1,4,5-

triphosphate (IP3). Released IP3 binds to their ryanodine receptors on the endoplasmic

reticulum, which leads to calcium release from this cellular stock. Both calcium and DAG

activates Protein Kinase C (PKC) and its effectors, such as Akt (also known as Protein kinase B,

PKB), or Extracellular signal-regulated kinases (ERK). ERK1/2 also known as mitogen actived

protein kinases (MAPK) and Akt are two convergent kinases reported in ASD [3, 5, 24]. G12/13

activates Rho Guanine exchange Factor (GEF) and RhoA, which acts on the cytoskeleton

promoting neurites formation. G proteins also participate in downstream signalling through

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TowardstheconvergenttherapeuticpotentialofGPCRsinautismspectrumdisordersAnilANNAMNEEDI1,2#,CarolineGORA1,AnaDUDAS1,XavierLERAY1,VéroniqueBOZON1,PascaleCREPIEUX1,LucieP.PELLISSIER1#1TeambiologyofGPCRSignalingsystems(BIOS),CNRS,IFCE,INRAE,UniversitédeTours,PRC,F-37380,Nouzilly,France.2LESTUDIUMLoireVa...

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Towards the convergent therapeutic potential of GPCR s in autism spectrum disorders Anil ANNAMNEEDI12 Caroline GORA1 Ana DUDAS1 Xavier LERAY1 Véronique BOZON1

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