Glial metabotropic glutamate receptor-4 increases maturation and survival of oligodendrocytes

Group III metabotropic glutamate (mGlu) receptors mediate important neuroprotective and anti-inflammatory effects. Stimulation of mGlu4 receptor reduces neuroinflammation in a mouse model of experimental autoimmune encephalomyelitis (EAE) whereas mGlu4 knockout mice display exacerbated EAE clinical...

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Main Authors:	Spampinato, Simona Federica, Merlo, Sara, Chisari, Mariangela, Nicoletti, Ferdinando, Sortino, Maria Angela
Format:	Online
Language:	English
Published:	Frontiers Media S.A. 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294134/

id	pubmed-4294134
recordtype	oai_dc
spelling	pubmed-42941342015-01-30 Glial metabotropic glutamate receptor-4 increases maturation and survival of oligodendrocytes Spampinato, Simona Federica Merlo, Sara Chisari, Mariangela Nicoletti, Ferdinando Sortino, Maria Angela Neuroscience Group III metabotropic glutamate (mGlu) receptors mediate important neuroprotective and anti-inflammatory effects. Stimulation of mGlu4 receptor reduces neuroinflammation in a mouse model of experimental autoimmune encephalomyelitis (EAE) whereas mGlu4 knockout mice display exacerbated EAE clinical scores. We now show that mGlu4 receptors are expressed in oligodendrocytes, astrocytes and microglia in culture. Oligodendrocytes express mGlu4 receptors only at early stages of maturation (O4 positive), but not when more differentiated (myelin basic protein, MBP positive). Treatment of immature oligodendrocytes with the mGlu4 receptor agonist L-2-Amino-4-phosphonobutyrate (L-AP4; 50 μM for 48 h) accelerates differentiation with enhanced branching and earlier appearance of MBP staining. Oligodendrocyte death induced by exposure to 1 mM kainic acid for 24 h is significantly reduced by a 30-min pretreatment with L-AP4 (50 μM), an effect observed only in the presence of astrocytes, mimicked by the specific mGlu4 receptor positive allosteric modulator N-Phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC) (30 μM) and prevented by pretreatment with the mGlu4 receptor antagonist, cyclopropyl-4-phosphonophenylglycine (CPPG) (100 μM). In astrocytes, mGlu4 receptor is the most expressed among group III mGlu receptors, as by Quantitative real time PCR (QRT-PCR), and its silencing prevents protective effects. Protection is also observed when conditioned medium (CM) from L-AP4-pretreated astrocytes is transferred to oligodendrocytes challenged with kainic acid. Transforming growth factor β (TGF-β) mediates the increased oligodendrocyte survival as the effect of L-AP4 is mimicked by addition of 10 ng/ml TGF-β and prevented by incubation with a neutralizing anti-TGF-β antibody. In contrast, despite the expression of mGlu4 receptor in resting and activated microglia, CM from L-AP4-stimulated microglia does not modify kainate-induced oligodendrocyte toxicity. Our results suggest that mGlu4 receptors expressed in astrocytes mediate enhanced survival of oligodendrocytes under conditions of excitotoxicity. Frontiers Media S.A. 2015-01-14 /pmc/articles/PMC4294134/ /pubmed/25642169 http://dx.doi.org/10.3389/fncel.2014.00462 Text en Copyright © 2015 Spampinato, Merlo, Chisari, Nicoletti and Sortino. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Spampinato, Simona Federica Merlo, Sara Chisari, Mariangela Nicoletti, Ferdinando Sortino, Maria Angela
spellingShingle	Spampinato, Simona Federica Merlo, Sara Chisari, Mariangela Nicoletti, Ferdinando Sortino, Maria Angela Glial metabotropic glutamate receptor-4 increases maturation and survival of oligodendrocytes
author_facet	Spampinato, Simona Federica Merlo, Sara Chisari, Mariangela Nicoletti, Ferdinando Sortino, Maria Angela
author_sort	Spampinato, Simona Federica
title	Glial metabotropic glutamate receptor-4 increases maturation and survival of oligodendrocytes
title_short	Glial metabotropic glutamate receptor-4 increases maturation and survival of oligodendrocytes
title_full	Glial metabotropic glutamate receptor-4 increases maturation and survival of oligodendrocytes
title_fullStr	Glial metabotropic glutamate receptor-4 increases maturation and survival of oligodendrocytes
title_full_unstemmed	Glial metabotropic glutamate receptor-4 increases maturation and survival of oligodendrocytes
title_sort	glial metabotropic glutamate receptor-4 increases maturation and survival of oligodendrocytes
description	Group III metabotropic glutamate (mGlu) receptors mediate important neuroprotective and anti-inflammatory effects. Stimulation of mGlu4 receptor reduces neuroinflammation in a mouse model of experimental autoimmune encephalomyelitis (EAE) whereas mGlu4 knockout mice display exacerbated EAE clinical scores. We now show that mGlu4 receptors are expressed in oligodendrocytes, astrocytes and microglia in culture. Oligodendrocytes express mGlu4 receptors only at early stages of maturation (O4 positive), but not when more differentiated (myelin basic protein, MBP positive). Treatment of immature oligodendrocytes with the mGlu4 receptor agonist L-2-Amino-4-phosphonobutyrate (L-AP4; 50 μM for 48 h) accelerates differentiation with enhanced branching and earlier appearance of MBP staining. Oligodendrocyte death induced by exposure to 1 mM kainic acid for 24 h is significantly reduced by a 30-min pretreatment with L-AP4 (50 μM), an effect observed only in the presence of astrocytes, mimicked by the specific mGlu4 receptor positive allosteric modulator N-Phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC) (30 μM) and prevented by pretreatment with the mGlu4 receptor antagonist, cyclopropyl-4-phosphonophenylglycine (CPPG) (100 μM). In astrocytes, mGlu4 receptor is the most expressed among group III mGlu receptors, as by Quantitative real time PCR (QRT-PCR), and its silencing prevents protective effects. Protection is also observed when conditioned medium (CM) from L-AP4-pretreated astrocytes is transferred to oligodendrocytes challenged with kainic acid. Transforming growth factor β (TGF-β) mediates the increased oligodendrocyte survival as the effect of L-AP4 is mimicked by addition of 10 ng/ml TGF-β and prevented by incubation with a neutralizing anti-TGF-β antibody. In contrast, despite the expression of mGlu4 receptor in resting and activated microglia, CM from L-AP4-stimulated microglia does not modify kainate-induced oligodendrocyte toxicity. Our results suggest that mGlu4 receptors expressed in astrocytes mediate enhanced survival of oligodendrocytes under conditions of excitotoxicity.
publisher	Frontiers Media S.A.
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294134/
_version_	1613176598019702784

Glial metabotropic glutamate receptor-4 increases maturation and survival of oligodendrocytes

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