Cerebral Expression of Metabotropic Glutamate Receptor Subtype 5 in Idiopathic Autism Spectrum Disorder and Fragile X Syndrome: A Pilot Study.

James Robert Brašić,Olivier Barret,Keith Slifer,John P Seibyl,Dejan B Budimirovic,Danna Jennings,Ayon Nandi,Dean F Wong,David S Russell,Samuel D Martin,Thomas Sedlak

doi:10.3390/ijms22062863

Abstract

Multiple lines of evidence suggest that dysfunction of the metabotropic glutamate receptor subtype 5 (mGluR5) plays a role in the pathogenesis of autism spectrum disorder (ASD). Yet animal and human investigations of mGluR5 expression provide conflicting findings about the nature of dysregulation of cerebral mGluR5 pathways in subtypes of ASD. The demonstration of reduced mGluR5 expression throughout the living brains of men with fragile X syndrome (FXS), the most common known single-gene cause of ASD, provides a clue to examine mGluR5 expression in ASD. We aimed to (A) compare and contrast mGluR5 expression in idiopathic autism spectrum disorder (IASD), FXS, and typical development (TD) and (B) show the value of positron emission tomography (PET) for the application of precision medicine for the diagnosis and treatment of individuals with IASD, FXS, and related conditions. Two teams of investigators independently administered 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB), a novel, specific mGluR5 PET ligand to quantitatively measure the density and the distribution of mGluR5s in the brain regions, to participants of both sexes with IASD and TD and men with FXS. In contrast to participants with TD, mGluR5 expression was significantly increased in the cortical regions of participants with IASD and significantly reduced in all regions of men with FXS. These results suggest the feasibility of this protocol as a valuable tool to measure mGluR5 expression in clinical trials of individuals with IASD and FXS and related conditions.

Highlights

Autism spectrum disorder (ASD) [1] comprises a heterogeneous group of neurodevelopmental disorders including (A) a subtype characterized by a behavioral phenotype with no known etiology [idiopathic autism spectrum disorder (IASD)] [2] and (B) medical disorders with known genetic etiologies [3], such as fragile X syndrome (FXS) [4]
We confirmed our earlier finding that metabotropic glutamate receptor subtype 5 (mGluR5) expression is reduced in all brain regions in men with FXS [17] on a sample of men with FXS compared to participants of both sexes with IASD [14,23] and typical development (TD) [14,17,25,26]
Reduced cortical mGluR5 expression may provide a basis for the cognitive deficits of individuals with FXS [56]

Summary

Introduction

Autism spectrum disorder (ASD) [1] comprises a heterogeneous group of neurodevelopmental disorders including (A) a subtype characterized by a behavioral phenotype with no known etiology [idiopathic autism spectrum disorder (IASD)] [2] and (B) medical disorders with known genetic etiologies [3], such as fragile X syndrome (FXS) [4]. FXS and some other subtypes of ASD are characterized by intellectual disability (ID) [6]. Dysfunction of protein synthesis mediated by abnormal pathways including metabotropic glutamate receptors (mGluR) plays a role in the pathometabolism of IASD [7,8] and FXS [9,10,11,12].

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