TGFβ signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults

Abstract Brain damage due to stroke or traumatic brain injury (TBI), both leading causes of serious long-term disability, often leads to the development of epilepsy. Patients who develop post-injury epilepsy tend to have poor functional outcomes. Emerging evidence highlights a potential role for blo...

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Autores principales:	Soo Young Kim, Vladimir V. Senatorov, Christapher S. Morrissey, Kristina Lippmann, Oscar Vazquez, Dan Z. Milikovsky, Feng Gu, Isabel Parada, David A. Prince, Albert J. Becker, Uwe Heinemann, Alon Friedman, Daniela Kaufer
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fbb888bc44be4410a0c2d072e5eab00a
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spelling	oai:doaj.org-article:fbb888bc44be4410a0c2d072e5eab00a2021-12-02T11:40:12ZTGFβ signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults10.1038/s41598-017-07394-32045-2322https://doaj.org/article/fbb888bc44be4410a0c2d072e5eab00a2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07394-3https://doaj.org/toc/2045-2322Abstract Brain damage due to stroke or traumatic brain injury (TBI), both leading causes of serious long-term disability, often leads to the development of epilepsy. Patients who develop post-injury epilepsy tend to have poor functional outcomes. Emerging evidence highlights a potential role for blood-brain barrier (BBB) dysfunction in the development of post-injury epilepsy. However, common mechanisms underlying the pathological hyperexcitability are largely unknown. Here, we show that comparative transcriptome analyses predict remodeling of extracellular matrix (ECM) as a common response to different types of injuries. ECM-related transcriptional changes were induced by the serum protein albumin via TGFβ signaling in primary astrocytes. In accordance with transcriptional responses, we found persistent degradation of protective ECM structures called perineuronal nets (PNNs) around fast-spiking inhibitory interneurons, in a rat model of TBI as well as in brains of human epileptic patients. Exposure of a naïve brain to albumin was sufficient to induce the transcriptional and translational upregulation of molecules related to ECM remodeling and the persistent breakdown of PNNs around fast-spiking inhibitory interneurons, which was contingent on TGFβ signaling activation. Our findings provide insights on how albumin extravasation that occurs upon BBB dysfunction in various brain injuries can predispose neural circuitry to the development of chronic inhibition deficits.Soo Young KimVladimir V. SenatorovChristapher S. MorrisseyKristina LippmannOscar VazquezDan Z. MilikovskyFeng GuIsabel ParadaDavid A. PrinceAlbert J. BeckerUwe HeinemannAlon FriedmanDaniela KauferNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Soo Young Kim Vladimir V. Senatorov Christapher S. Morrissey Kristina Lippmann Oscar Vazquez Dan Z. Milikovsky Feng Gu Isabel Parada David A. Prince Albert J. Becker Uwe Heinemann Alon Friedman Daniela Kaufer TGFβ signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults
description	Abstract Brain damage due to stroke or traumatic brain injury (TBI), both leading causes of serious long-term disability, often leads to the development of epilepsy. Patients who develop post-injury epilepsy tend to have poor functional outcomes. Emerging evidence highlights a potential role for blood-brain barrier (BBB) dysfunction in the development of post-injury epilepsy. However, common mechanisms underlying the pathological hyperexcitability are largely unknown. Here, we show that comparative transcriptome analyses predict remodeling of extracellular matrix (ECM) as a common response to different types of injuries. ECM-related transcriptional changes were induced by the serum protein albumin via TGFβ signaling in primary astrocytes. In accordance with transcriptional responses, we found persistent degradation of protective ECM structures called perineuronal nets (PNNs) around fast-spiking inhibitory interneurons, in a rat model of TBI as well as in brains of human epileptic patients. Exposure of a naïve brain to albumin was sufficient to induce the transcriptional and translational upregulation of molecules related to ECM remodeling and the persistent breakdown of PNNs around fast-spiking inhibitory interneurons, which was contingent on TGFβ signaling activation. Our findings provide insights on how albumin extravasation that occurs upon BBB dysfunction in various brain injuries can predispose neural circuitry to the development of chronic inhibition deficits.
format	article
author	Soo Young Kim Vladimir V. Senatorov Christapher S. Morrissey Kristina Lippmann Oscar Vazquez Dan Z. Milikovsky Feng Gu Isabel Parada David A. Prince Albert J. Becker Uwe Heinemann Alon Friedman Daniela Kaufer
author_facet	Soo Young Kim Vladimir V. Senatorov Christapher S. Morrissey Kristina Lippmann Oscar Vazquez Dan Z. Milikovsky Feng Gu Isabel Parada David A. Prince Albert J. Becker Uwe Heinemann Alon Friedman Daniela Kaufer
author_sort	Soo Young Kim
title	TGFβ signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults
title_short	TGFβ signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults
title_full	TGFβ signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults
title_fullStr	TGFβ signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults
title_full_unstemmed	TGFβ signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults
title_sort	tgfβ signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/fbb888bc44be4410a0c2d072e5eab00a
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TGFβ signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults

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