mGlu1 potentiation enhances prelimbic somatostatin interneuron activity to rescue schizophrenia-like physiological and cognitive deficits

Summary: Evidence for prefrontal cortical (PFC) GABAergic dysfunction is one of the most consistent findings in schizophrenia and may contribute to cognitive deficits. Recent studies suggest that the mGlu1 subtype of metabotropic glutamate receptor regulates cortical inhibition; however, understandi...

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Autores principales:	James Maksymetz, Nellie E. Byun, Deborah J. Luessen, Brianna Li, Robert L. Barry, John C. Gore, Colleen M. Niswender, Craig W. Lindsley, Max E. Joffe, P. Jeffrey Conn
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	metabotropic glutamate receptor mGlu1 prefrontal cortex inhibitory transmission somatostatin interneurons excitation-inhibition balance Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/a075ccbe92734d68bafa119211f41b75
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spelling	oai:doaj.org-article:a075ccbe92734d68bafa119211f41b752021-11-04T04:29:45ZmGlu1 potentiation enhances prelimbic somatostatin interneuron activity to rescue schizophrenia-like physiological and cognitive deficits2211-124710.1016/j.celrep.2021.109950https://doaj.org/article/a075ccbe92734d68bafa119211f41b752021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2211124721014273https://doaj.org/toc/2211-1247Summary: Evidence for prefrontal cortical (PFC) GABAergic dysfunction is one of the most consistent findings in schizophrenia and may contribute to cognitive deficits. Recent studies suggest that the mGlu1 subtype of metabotropic glutamate receptor regulates cortical inhibition; however, understanding the mechanisms through which mGlu1 positive allosteric modulators (PAMs) regulate PFC microcircuit function and cognition is essential for advancing these potential therapeutics toward the clinic. We report a series of electrophysiology, optogenetic, pharmacological magnetic resonance imaging, and animal behavior studies demonstrating that activation of mGlu1 receptors increases inhibitory transmission in the prelimbic PFC by selective excitation of somatostatin-expressing interneurons (SST-INs). An mGlu1 PAM reverses cortical hyperactivity and concomitant cognitive deficits induced by N-methyl-d-aspartate (NMDA) receptor antagonists. Using in vivo optogenetics, we show that prelimbic SST-INs are necessary for mGlu1 PAM efficacy. Collectively, these findings suggest that mGlu1 PAMs could reverse cortical GABAergic deficits and exhibit efficacy in treating cognitive dysfunction in schizophrenia.James MaksymetzNellie E. ByunDeborah J. LuessenBrianna LiRobert L. BarryJohn C. GoreColleen M. NiswenderCraig W. LindsleyMax E. JoffeP. Jeffrey ConnElsevierarticlemetabotropic glutamate receptormGlu1prefrontal cortexinhibitory transmissionsomatostatin interneuronsexcitation-inhibition balanceBiology (General)QH301-705.5ENCell Reports, Vol 37, Iss 5, Pp 109950- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	metabotropic glutamate receptor mGlu1 prefrontal cortex inhibitory transmission somatostatin interneurons excitation-inhibition balance Biology (General) QH301-705.5
spellingShingle	metabotropic glutamate receptor mGlu1 prefrontal cortex inhibitory transmission somatostatin interneurons excitation-inhibition balance Biology (General) QH301-705.5 James Maksymetz Nellie E. Byun Deborah J. Luessen Brianna Li Robert L. Barry John C. Gore Colleen M. Niswender Craig W. Lindsley Max E. Joffe P. Jeffrey Conn mGlu1 potentiation enhances prelimbic somatostatin interneuron activity to rescue schizophrenia-like physiological and cognitive deficits
description	Summary: Evidence for prefrontal cortical (PFC) GABAergic dysfunction is one of the most consistent findings in schizophrenia and may contribute to cognitive deficits. Recent studies suggest that the mGlu1 subtype of metabotropic glutamate receptor regulates cortical inhibition; however, understanding the mechanisms through which mGlu1 positive allosteric modulators (PAMs) regulate PFC microcircuit function and cognition is essential for advancing these potential therapeutics toward the clinic. We report a series of electrophysiology, optogenetic, pharmacological magnetic resonance imaging, and animal behavior studies demonstrating that activation of mGlu1 receptors increases inhibitory transmission in the prelimbic PFC by selective excitation of somatostatin-expressing interneurons (SST-INs). An mGlu1 PAM reverses cortical hyperactivity and concomitant cognitive deficits induced by N-methyl-d-aspartate (NMDA) receptor antagonists. Using in vivo optogenetics, we show that prelimbic SST-INs are necessary for mGlu1 PAM efficacy. Collectively, these findings suggest that mGlu1 PAMs could reverse cortical GABAergic deficits and exhibit efficacy in treating cognitive dysfunction in schizophrenia.
format	article
author	James Maksymetz Nellie E. Byun Deborah J. Luessen Brianna Li Robert L. Barry John C. Gore Colleen M. Niswender Craig W. Lindsley Max E. Joffe P. Jeffrey Conn
author_facet	James Maksymetz Nellie E. Byun Deborah J. Luessen Brianna Li Robert L. Barry John C. Gore Colleen M. Niswender Craig W. Lindsley Max E. Joffe P. Jeffrey Conn
author_sort	James Maksymetz
title	mGlu1 potentiation enhances prelimbic somatostatin interneuron activity to rescue schizophrenia-like physiological and cognitive deficits
title_short	mGlu1 potentiation enhances prelimbic somatostatin interneuron activity to rescue schizophrenia-like physiological and cognitive deficits
title_full	mGlu1 potentiation enhances prelimbic somatostatin interneuron activity to rescue schizophrenia-like physiological and cognitive deficits
title_fullStr	mGlu1 potentiation enhances prelimbic somatostatin interneuron activity to rescue schizophrenia-like physiological and cognitive deficits
title_full_unstemmed	mGlu1 potentiation enhances prelimbic somatostatin interneuron activity to rescue schizophrenia-like physiological and cognitive deficits
title_sort	mglu1 potentiation enhances prelimbic somatostatin interneuron activity to rescue schizophrenia-like physiological and cognitive deficits
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/a075ccbe92734d68bafa119211f41b75
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mGlu1 potentiation enhances prelimbic somatostatin interneuron activity to rescue schizophrenia-like physiological and cognitive deficits

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