mGluR5 hypofunction is integral to glutamatergic dysregulation in schizophrenia.
Aged
Aged, 80 and over
Antipsychotic Agents
/ therapeutic use
Brain
/ metabolism
Excitatory Amino Acid Agents
/ metabolism
Female
Humans
Male
Membrane Proteins
/ metabolism
Phosphorylation
Post-Synaptic Density
/ metabolism
Prefrontal Cortex
/ metabolism
Receptor, Metabotropic Glutamate 5
/ metabolism
Receptors, N-Methyl-D-Aspartate
/ metabolism
Schizophrenia
/ metabolism
Signal Transduction
/ drug effects
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
25
04
2018
accepted:
09
07
2018
revised:
18
06
2018
pubmed:
15
9
2018
medline:
18
2
2021
entrez:
15
9
2018
Statut:
ppublish
Résumé
Multiple lines of evidence point to glutamatergic signaling in the postsynaptic density (PSD) as a pathophysiologic mechanism in schizophrenia. Integral to PSD glutamatergic signaling is reciprocal interplay between GluN and mGluR5 signaling. We examined agonist-induced mGluR5 signaling in the postmortem dorsolateral prefrontal cortex (DLPFC) derived from 17 patients and age-matched and sex-matched controls. The patient group showed a striking reduction in mGluR5 signaling, manifested by decreases in Gq/11 coupling and association with PI3K and Homer compared to controls (p < 0.01 for all). This was accompanied by increases in serine and tyrosine phosphorylation of mGluR5, which can decrease mGluR5 activity via desensitization (p < 0.01). In addition, we find altered protein-protein interaction (PPI) of mGluR5 with RGS4, norbin, Preso 1 and tamalin, which can also attenuate mGluR5 activity. We previously reported molecular underpinnings of GluN hypofunction (decreased GluN2 phosphorylation) and here we show those of reduced mGluR5 signaling in schizophrenia. We find that reduced GluN2 phosphorylation can be precipitated by attenuated mGluR5 activity and that increased mGluR5 phosphorylation can result from decreased GluN function, suggesting a reciprocal interplay between the two pathways in schizophrenia. Interestingly, the patient group showed decreased mGluR5-GluN association (p < 0.01), a mechanistic basis for the reciprocal facilitation. In sum, we present the first direct evidence for mGluR5 hypoactivity, propose a reciprocal interplay between GluN and mGluR5 pathways as integral to glutamatergic dysregulation and suggest protein-protein interactions in mGluR5-GluN complexes as potential targets for intervention in schizophrenia.
Identifiants
pubmed: 30214040
doi: 10.1038/s41380-018-0234-y
pii: 10.1038/s41380-018-0234-y
pmc: PMC7500805
mid: NIHMS980546
doi:
Substances chimiques
Antipsychotic Agents
0
Excitatory Amino Acid Agents
0
GRM5 protein, human
0
Membrane Proteins
0
Receptor, Metabotropic Glutamate 5
0
Receptors, N-Methyl-D-Aspartate
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
750-760Subventions
Organisme : NIMH NIH HHS
ID : R01 MH075916
Pays : United States
Organisme : NIH HHS
ID : S10 OD010380
Pays : United States
Organisme : NIMH NIH HHS
ID : P50 MH096891
Pays : United States
Organisme : NCATS NIH HHS
ID : KL2 TR001854
Pays : United States
Organisme : NIH HHS
ID : S10 OD018522
Pays : United States
Organisme : NIH HHS
ID : S10 OD026880
Pays : United States
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