PAFAH1B1 haploinsufficiency disrupts GABA neurons and synaptic E/I balance in the dentate gyrus

Abstract Hemizygous mutations in the human gene encoding platelet-activating factor acetylhydrolase IB subunit alpha (Pafah1b1), also called Lissencephaly-1, can cause classical lissencephaly, a severe malformation of cortical development. Children with this disorder suffer from deficits in neuronal...

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Autores principales:	Matthew T. Dinday, Kelly M. Girskis, Sunyoung Lee, Scott C. Baraban, Robert F. Hunt
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3b5b7da363c540d1b3dea4e151e4f974
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spelling	oai:doaj.org-article:3b5b7da363c540d1b3dea4e151e4f9742021-12-02T15:05:54ZPAFAH1B1 haploinsufficiency disrupts GABA neurons and synaptic E/I balance in the dentate gyrus10.1038/s41598-017-08809-x2045-2322https://doaj.org/article/3b5b7da363c540d1b3dea4e151e4f9742017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08809-xhttps://doaj.org/toc/2045-2322Abstract Hemizygous mutations in the human gene encoding platelet-activating factor acetylhydrolase IB subunit alpha (Pafah1b1), also called Lissencephaly-1, can cause classical lissencephaly, a severe malformation of cortical development. Children with this disorder suffer from deficits in neuronal migration, severe intellectual disability, intractable epilepsy and early death. While many of these features can be reproduced in Pafah1b1+/− mice, the impact of Pafah1b1+/− on the function of individual subpopulations of neurons and ultimately brain circuits is largely unknown. Here, we show tangential migration of young GABAergic interneurons into the developing hippocampus is slowed in Pafah1b1+/− mice. Mutant mice had a decreased density of parvalbumin- and somatostatin-positive interneurons in dentate gyrus, but no change in density of calretinin interneurons. Whole-cell patch-clamp recordings revealed increased excitatory and decreased inhibitory synaptic inputs onto granule cells of Pafah1b1+/− mice. Mutant animals developed spontaneous electrographic seizures, as well as long-term deficits in contextual memory. Our findings provide evidence of a dramatic shift in excitability in the dentate gyrus of Pafah1b1+/− mice that may contribute to epilepsy or cognitive impairments associated with lissencephaly.Matthew T. DindayKelly M. GirskisSunyoung LeeScott C. BarabanRobert F. HuntNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Matthew T. Dinday Kelly M. Girskis Sunyoung Lee Scott C. Baraban Robert F. Hunt PAFAH1B1 haploinsufficiency disrupts GABA neurons and synaptic E/I balance in the dentate gyrus
description	Abstract Hemizygous mutations in the human gene encoding platelet-activating factor acetylhydrolase IB subunit alpha (Pafah1b1), also called Lissencephaly-1, can cause classical lissencephaly, a severe malformation of cortical development. Children with this disorder suffer from deficits in neuronal migration, severe intellectual disability, intractable epilepsy and early death. While many of these features can be reproduced in Pafah1b1+/− mice, the impact of Pafah1b1+/− on the function of individual subpopulations of neurons and ultimately brain circuits is largely unknown. Here, we show tangential migration of young GABAergic interneurons into the developing hippocampus is slowed in Pafah1b1+/− mice. Mutant mice had a decreased density of parvalbumin- and somatostatin-positive interneurons in dentate gyrus, but no change in density of calretinin interneurons. Whole-cell patch-clamp recordings revealed increased excitatory and decreased inhibitory synaptic inputs onto granule cells of Pafah1b1+/− mice. Mutant animals developed spontaneous electrographic seizures, as well as long-term deficits in contextual memory. Our findings provide evidence of a dramatic shift in excitability in the dentate gyrus of Pafah1b1+/− mice that may contribute to epilepsy or cognitive impairments associated with lissencephaly.
format	article
author	Matthew T. Dinday Kelly M. Girskis Sunyoung Lee Scott C. Baraban Robert F. Hunt
author_facet	Matthew T. Dinday Kelly M. Girskis Sunyoung Lee Scott C. Baraban Robert F. Hunt
author_sort	Matthew T. Dinday
title	PAFAH1B1 haploinsufficiency disrupts GABA neurons and synaptic E/I balance in the dentate gyrus
title_short	PAFAH1B1 haploinsufficiency disrupts GABA neurons and synaptic E/I balance in the dentate gyrus
title_full	PAFAH1B1 haploinsufficiency disrupts GABA neurons and synaptic E/I balance in the dentate gyrus
title_fullStr	PAFAH1B1 haploinsufficiency disrupts GABA neurons and synaptic E/I balance in the dentate gyrus
title_full_unstemmed	PAFAH1B1 haploinsufficiency disrupts GABA neurons and synaptic E/I balance in the dentate gyrus
title_sort	pafah1b1 haploinsufficiency disrupts gaba neurons and synaptic e/i balance in the dentate gyrus
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/3b5b7da363c540d1b3dea4e151e4f974
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PAFAH1B1 haploinsufficiency disrupts GABA neurons and synaptic E/I balance in the dentate gyrus

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