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Principal Investigator: Chang-Gyu Hahn
Organization: THOMAS JEFFERSON UNIVERSITY
Fiscal Year: 2024
Award: $609,276
Funding agency: National Institute of Mental Health
Project Summary
(Significance) Multiple lines of evidence have implicated mGluR5 signaling for the pathophysiology and
treatment of schizophrenia; yet possible dysregulation of mGluR5 signaling and their pathophysiologic roles
are presently unknown. Recently, we found direct evidence for reduced mGluR5 signaling in the postmortem
dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia. mGluR5 is physically connected with
NMDA receptor (GluN) complexes in the postsynaptic density (PSD) and these two pathways facilitate the
activity of each other. (Preliminary Studies) We examined the agonist-induced activation of mGluR5 signaling
in the postmortem dorsolateral prefrontal cortex (DLPFC) derived from 17 matched pairs of patients and
controls. We found a striking reduction in three pathways downstream to mGluR5 receptor activation; namely,
Gq/11 activation and recruitment of PI3K and scaffolding proteins compared to controls (P<0.01). This
dysregulation was accompanied by alterations in phosphorylation of mGluR5, important for receptor
desensitization, and in mGluR5 association with RGS4, Preso 1, norbin and tamalin, which are critical for
surface expression and clustering. Importantly, we find evidence supporting disruption of reciprocal facilitation
between mGluR5 and GluN signaling in schizophrenia and thus hypofunction of one can further compromise
the other. (Scientific Premise) Schizophrenia is associated with mGluR5 signaling hypoactivity mediated by
altered mGluR5 phosphorylation and protein – protein interactions (PrPrIs) in the receptor complexes. mGluR5
hypofunction can contribute to GluN signaling hypoactivity and vice versa via disruption of reciprocal
facilitation. PrPrIs in the interactome may be a point of convergence for etiologic factors. (Specific Aims) To
further characterize mGluR5 hypoactivity and its interplay with GluN signaling in schizophrenia, we will
examine molecular underpinnings for mGluR5 hypoactivity on GluN signaling and vice versa in the DLPFC of
patients compared to controls. (Aim 1). Our preliminary data and recent studies point to PrPrIs as substrates
upon which various molecular alterations converge and precipitate glutamatergic dysregulation. Combining
discovery and quantitative proteomics, we will analyze PrPrI alterations in the mGluR5-GluN interactome in
patients at the basal level and in response to receptor activation (Aim 2). PrPrI alterations in the interactome
can be traced to their etiologic underpinnings at the genomic, transcriptomic and proteomic levels. Cutting
edge systems biology algorithms permit us to leverage largest genomics data sets presently available and
impute DLPFC transcriptomics data of the same number of subjects. Genetic variants, imputed transcriptomic
results, along with quantitative PSD proteomics results will be projected onto the interactome using heat
diffusion based algorithms (Aim 3). This will identify etiologically significant and potentially targetable
subnetworks in the interactome. (Impact) We will establish mGluR5 hypofunction as integral to glutamatergic
dysregulation in schizophrenia and identify etiologic underpinnings and potential points of intervention.
Terms: <1-Phosphatidylinositol 3-Kinase><ATAC sequencing><ATAC-seq><ATACseq><Age><Agonist><Algorithms><Aminoacetic Acid><Assay for Transposase-Accessible Chromatin using sequencing><Attenuated><Autopsy><Body Tissues><Brain><Brain Nervous System><Brain region><Calcineurin><Causality><Cell Communication and Signaling><Cell Signaling><Chromatin><Complex><Coupling><Data><Data Set><Diffusion><Disease><Disorder><Dysfunction><Encephalon><Etiology><Event><Functional disorder><GRASP gene><GRASP protein><GRP1- Associated Scaffold Protein><GWA study><GWAS><Gene variant><Genetic study><Genomics><Glutamates><Glycine><Incubated><Individual><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Investigation><L-Glutamate><Label><Link><Macromolecular Complexes><Mediating><Methods><Mind><Molecular><Molecular Fingerprinting><Molecular Profiling><N Methyl D aspartic Acid><N methyl D aspartate><N-Methyl-D-Aspartate Receptors><N-Methyl-D-aspartate><N-Methylaspartate><N-Methylaspartate Receptors><NMDA><NMDA Receptor-Ionophore Complex><NMDA Receptors><PI-3 Kinase><PI3-Kinase><PI3CG><PI3KGamma><PI3k><PIK3><PIK3CG><PIK3CG gene><PP2B><Pathway interactions><Patients><Pennsylvania><Phenotype><Phosphatidylinositol 3-Kinase><Phosphatidylinositol-3-OH Kinase><Phosphoinositide 3-Hydroxykinase><Phosphorylation><Physiopathology><Prefrontal Cortex><Process><Protein Phosphatase-2B><Protein Phosphorylation><Proteins><Proteomics><PtdIns 3-Kinase><RNA Seq><RNA sequencing><RNAseq><Receptor Activation><Receptor Protein><Reporting><Risk-associated variant><Role><Scaffolding Protein><Schizophrenia><Schizophrenic Disorders><Shotguns><Signal Transduction><Signal Transduction Systems><Signaling><Surface><System><Systems Biology><Tamalin><Tissues><Type I Phosphatidylinositol Kinase><Type III Phosphoinositide 3-Kinase><Universities><Variant><Variation><Veterans><ages><allele variant><allelic variant><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><attenuate><attenuates><attenuation><biological signal transduction><causation><cohort><compare to control><comparison control><dementia praecox><density><desensitization><design><designing><diffused><diffuses><diffusing><diffusions><disease causation><disease phenotype><gene network><genetic variant><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><genomic data><genomic data-set><genomic dataset><genomic variant><glutamate signaling><glutamatergic><glutamatergic dendrodendritic synapses><glutamatergic signaling><innovate><innovation><innovative><interventional strategy><molecular profile><molecular signature><necropsy><novel><pathophysiology><pathway><postmortem><postsynaptic><programs><protein complex><protein protein interaction><psychiatric genomics><receptor><recruit><response><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><schizophrenia risk><schizophrenic><sex><shot gun><social role><trait><transcriptome sequencing><transcriptomic sequencing><transcriptomics><virtual><whole genome association analysis><whole genome association studies><whole genome association study>