Reelin secreted by GABAergic neurons regulates glutamate receptor homeostasis.

<h4>Background</h4>Reelin is a large secreted protein of the extracellular matrix that has been proposed to participate to the etiology of schizophrenia. During development, reelin is crucial for the correct cytoarchitecture of laminated brain structures and is produced by a subset of ne...

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Autores principales:	Cecilia Gonzalez Campo, Mélanie Sinagra, Danièle Verrier, Olivier J Manzoni, Pascale Chavis
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/10114170abd542718c87b246114861fa
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spelling	oai:doaj.org-article:10114170abd542718c87b246114861fa2021-11-25T06:22:46ZReelin secreted by GABAergic neurons regulates glutamate receptor homeostasis.1932-620310.1371/journal.pone.0005505https://doaj.org/article/10114170abd542718c87b246114861fa2009-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19430527/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Reelin is a large secreted protein of the extracellular matrix that has been proposed to participate to the etiology of schizophrenia. During development, reelin is crucial for the correct cytoarchitecture of laminated brain structures and is produced by a subset of neurons named Cajal-Retzius. After birth, most of these cells degenerate and reelin expression persists in postnatal and adult brain. The phenotype of neurons that bind secreted reelin and whether the continuous secretion of reelin is required for physiological functions at postnatal stages remain unknown.<h4>Methodology/principal findings</h4>Combining immunocytochemical and pharmacological approaches, we first report that two distinct patterns of reelin expression are present in cultured hippocampal neurons. We show that in hippocampal cultures, reelin is secreted by GABAergic neurons displaying an intense reelin immunoreactivity (IR). We demonstrate that secreted reelin binds to receptors of the lipoprotein family on neurons with a punctate reelin IR. Secondly, using calcium imaging techniques, we examined the physiological consequences of reelin secretion blockade. Blocking protein secretion rapidly and reversibly changes the subunit composition of N-methyl-D-aspartate glutamate receptors (NMDARs) to a predominance of NR2B-containing NMDARs. Addition of recombinant or endogenously secreted reelin rescues the effects of protein secretion blockade and reverts the fraction of NR2B-containing NMDARs to control levels. Therefore, the continuous secretion of reelin is necessary to control the subunit composition of NMDARs in hippocampal neurons.<h4>Conclusions/significance</h4>Our data show that the heterogeneity of reelin immunoreactivity correlates with distinct functional populations: neurons synthesizing and secreting reelin and/or neurons binding reelin. Furthermore, we show that continuous reelin secretion is a strict requirement to maintain the composition of NMDARs. We propose that reelin is a trans-neuronal messenger secreted by GABAergic neurons that regulates NMDARs homeostasis in postnatal hippocampus. Defects in reelin secretion could play a major role in the development of neuropsychiatric disorders, particularly those associated with deregulation of NMDARs such as schizophrenia.Cecilia Gonzalez CampoMélanie SinagraDanièle VerrierOlivier J ManzoniPascale ChavisPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 4, Iss 5, p e5505 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Cecilia Gonzalez Campo Mélanie Sinagra Danièle Verrier Olivier J Manzoni Pascale Chavis Reelin secreted by GABAergic neurons regulates glutamate receptor homeostasis.
description	<h4>Background</h4>Reelin is a large secreted protein of the extracellular matrix that has been proposed to participate to the etiology of schizophrenia. During development, reelin is crucial for the correct cytoarchitecture of laminated brain structures and is produced by a subset of neurons named Cajal-Retzius. After birth, most of these cells degenerate and reelin expression persists in postnatal and adult brain. The phenotype of neurons that bind secreted reelin and whether the continuous secretion of reelin is required for physiological functions at postnatal stages remain unknown.<h4>Methodology/principal findings</h4>Combining immunocytochemical and pharmacological approaches, we first report that two distinct patterns of reelin expression are present in cultured hippocampal neurons. We show that in hippocampal cultures, reelin is secreted by GABAergic neurons displaying an intense reelin immunoreactivity (IR). We demonstrate that secreted reelin binds to receptors of the lipoprotein family on neurons with a punctate reelin IR. Secondly, using calcium imaging techniques, we examined the physiological consequences of reelin secretion blockade. Blocking protein secretion rapidly and reversibly changes the subunit composition of N-methyl-D-aspartate glutamate receptors (NMDARs) to a predominance of NR2B-containing NMDARs. Addition of recombinant or endogenously secreted reelin rescues the effects of protein secretion blockade and reverts the fraction of NR2B-containing NMDARs to control levels. Therefore, the continuous secretion of reelin is necessary to control the subunit composition of NMDARs in hippocampal neurons.<h4>Conclusions/significance</h4>Our data show that the heterogeneity of reelin immunoreactivity correlates with distinct functional populations: neurons synthesizing and secreting reelin and/or neurons binding reelin. Furthermore, we show that continuous reelin secretion is a strict requirement to maintain the composition of NMDARs. We propose that reelin is a trans-neuronal messenger secreted by GABAergic neurons that regulates NMDARs homeostasis in postnatal hippocampus. Defects in reelin secretion could play a major role in the development of neuropsychiatric disorders, particularly those associated with deregulation of NMDARs such as schizophrenia.
format	article
author	Cecilia Gonzalez Campo Mélanie Sinagra Danièle Verrier Olivier J Manzoni Pascale Chavis
author_facet	Cecilia Gonzalez Campo Mélanie Sinagra Danièle Verrier Olivier J Manzoni Pascale Chavis
author_sort	Cecilia Gonzalez Campo
title	Reelin secreted by GABAergic neurons regulates glutamate receptor homeostasis.
title_short	Reelin secreted by GABAergic neurons regulates glutamate receptor homeostasis.
title_full	Reelin secreted by GABAergic neurons regulates glutamate receptor homeostasis.
title_fullStr	Reelin secreted by GABAergic neurons regulates glutamate receptor homeostasis.
title_full_unstemmed	Reelin secreted by GABAergic neurons regulates glutamate receptor homeostasis.
title_sort	reelin secreted by gabaergic neurons regulates glutamate receptor homeostasis.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/10114170abd542718c87b246114861fa
work_keys_str_mv	AT ceciliagonzalezcampo reelinsecretedbygabaergicneuronsregulatesglutamatereceptorhomeostasis AT melaniesinagra reelinsecretedbygabaergicneuronsregulatesglutamatereceptorhomeostasis AT danieleverrier reelinsecretedbygabaergicneuronsregulatesglutamatereceptorhomeostasis AT olivierjmanzoni reelinsecretedbygabaergicneuronsregulatesglutamatereceptorhomeostasis AT pascalechavis reelinsecretedbygabaergicneuronsregulatesglutamatereceptorhomeostasis
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Reelin secreted by GABAergic neurons regulates glutamate receptor homeostasis.

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