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Activation of Metabotropic Glutamate Receptor 3 Modulates Thalamo-accumbal Transmission and Rescues Schizophrenia-Like Physiological and Behavioral Deficits.

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العنوان: Activation of Metabotropic Glutamate Receptor 3 Modulates Thalamo-accumbal Transmission and Rescues Schizophrenia-Like Physiological and Behavioral Deficits.
المؤلفون: Dogra S; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee. Electronic address: shalini.dogra@vanderbilt.edu., Aguayo C; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee., Xiang Z; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee., Putnam J; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee., Smith J; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee., Johnston C; Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina., Foster DJ; Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina., Lindsley CW; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee; Department of Chemistry, Vanderbilt University, Nashville, Tennessee; Vanderbilt Institute for Chemical Biology, Vanderbilt University, Nashville, Tennessee., Niswender CM; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee; Vanderbilt Kennedy Center, Vanderbilt University, Nashville, Tennessee; Vanderbilt Institute for Chemical Biology, Vanderbilt University, Nashville, Tennessee., Conn PJ; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee; Vanderbilt Kennedy Center, Vanderbilt University, Nashville, Tennessee; Vanderbilt Institute for Chemical Biology, Vanderbilt University, Nashville, Tennessee. Electronic address: jeff.conn@vanderbilt.edu.
المصدر: Biological psychiatry [Biol Psychiatry] 2024 Aug 01; Vol. 96 (3), pp. 230-242. Date of Electronic Publication: 2023 Dec 05.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: United States NLM ID: 0213264 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-2402 (Electronic) Linking ISSN: 00063223 NLM ISO Abbreviation: Biol Psychiatry Subsets: MEDLINE
أسماء مطبوعة: Publication: New York, NY : Elsevier
Original Publication: New York, Plenum Pub. Corp.
مواضيع طبية MeSH: Schizophrenia*/metabolism , Schizophrenia*/physiopathology , Receptors, Metabotropic Glutamate*/metabolism , Receptors, Metabotropic Glutamate*/agonists , Nucleus Accumbens*/drug effects , Nucleus Accumbens*/metabolism , Thalamus*/drug effects , Thalamus*/metabolism , Synaptic Transmission*/drug effects , Synaptic Transmission*/physiology , Phencyclidine*/pharmacology, Animals ; Mice ; Male ; Mice, Inbred C57BL ; Optogenetics ; Disease Models, Animal ; Receptors, Dopamine D1/metabolism ; Receptors, Dopamine D1/agonists ; Social Behavior ; Behavior, Animal/drug effects
مستخلص: Background: Polymorphisms in the gene encoding for metabotropic glutamate receptor 3 (mGlu 3 ) are associated with an increased likelihood of schizophrenia diagnosis and can predict improvements in negative symptoms following treatment with antipsychotics. However, the mechanisms by which mGlu 3 can regulate brain circuits involved in schizophrenia pathophysiology are not clear.
Methods: We employed selective pharmacological tools and a variety of approaches including whole-cell patch-clamp electrophysiology, slice optogenetics, and fiber photometry to investigate the effects of mGlu 3 activation on phencyclidine (PCP)-induced impairments in thalamo-accumbal transmission and sociability deficits. A chemogenetic approach was used to evaluate the role of thalamo-accumbal transmission in PCP-induced sociability deficits.
Results: We first established that PCP treatment augmented excitatory transmission onto dopamine D 1 receptor-expressing medium spiny neurons (D1-MSNs) in the nucleus accumbens (NAc) and induced sociability deficits. Our studies revealed a selective increase in glutamatergic synaptic transmission from thalamic afferents to D1-MSNs in the NAc shell. Chemogenetic silencing of thalamo-accumbal inputs rescued PCP-induced sociability deficits. Pharmacological activation of mGlu 3 normalized PCP-induced impairments in thalamo-accumbal transmission and sociability deficits. Mechanistic studies revealed that mGlu 3 activation induced robust long-term depression at synapses from the thalamic projections onto D1-MSNs in the NAc shell.
Conclusions: These data demonstrate that activation of mGlu 3 decreases thalamo-accumbal transmission and thereby rescues sociability deficits in mouse modeling schizophrenia-like symptoms. These findings provide novel insights into the NAc-specific mechanisms and suggest that agents modulating glutamatergic signaling in the NAc may provide a promising approach for treating negative symptoms in schizophrenia.
(Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
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معلومات مُعتمدة: R01 MH062646 United States MH NIMH NIH HHS; P30 DK058404 United States DK NIDDK NIH HHS; R01 NS031373 United States NS NINDS NIH HHS; P30 EY008126 United States EY NEI NIH HHS; P30 DK020593 United States DK NIDDK NIH HHS; P30 CA068485 United States CA NCI NIH HHS; P50 HD103537 United States HD NICHD NIH HHS; R37 NS031373 United States NS NINDS NIH HHS; U24 DK059637 United States DK NIDDK NIH HHS
فهرسة مساهمة: Keywords: Negative symptoms; Nucleus accumbens; Schizophrenia; Synaptic plasticity; Thalamo-accumbal transmission; mGlu(3)
المشرفين على المادة: 0 (Receptors, Metabotropic Glutamate)
0 (metabotropic glutamate receptor 3)
J1DOI7UV76 (Phencyclidine)
0 (Receptors, Dopamine D1)
تواريخ الأحداث: Date Created: 20231207 Date Completed: 20240710 Latest Revision: 20240806
رمز التحديث: 20240806
مُعرف محوري في PubMed: PMC11150332
DOI: 10.1016/j.biopsych.2023.11.023
PMID: 38061467
قاعدة البيانات: MEDLINE
الوصف
تدمد:1873-2402
DOI:10.1016/j.biopsych.2023.11.023