Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus

Autores
Hussain, Tabish; Kil, Hyunsuk; Hattiangady, Bharathi; Lee, Jaeho; Kodali, Maheedhar; Shuai, Bing; Attaluri, Sahithi; Takata, Yoko; Shen, Jianjun; Abba, Martín Carlos; Shetty, Ashok K.; Aldaz, Claudio Marcelo
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The association of WW domain-containing oxidoreductase WWOX gene loss of function with central nervous system (CNS) related pathologies is well documented. These include spinocerebellar ataxia, epilepsy and mental retardation (SCAR12, OMIM: 614322) and early infantile epileptic encephalopathy (EIEE28, OMIM: 616211) syndromes. However, there is complete lack of understanding of the pathophysiological mechanisms at play. In this study, using a Wwox knockout (Wwox KO) mouse model (2 weeks old, both sexes) and stereological studies we observe that Wwox deletion leads to a significant reduction in the number of hippocampal GABA-ergic (γ-aminobutyric acid) interneurons. Wwox KO mice displayed significantly reduced numbers of calcium-binding protein parvalbumin (PV) and neuropeptide Y (NPY) expressing interneurons in different subfields of the hippocampus in comparison to Wwox wild-type (WT) mice. We also detected decreased levels of Glutamic Acid Decarboxylase protein isoforms GAD65/67 expression in Wwox null hippocampi suggesting lower levels of GABA synthesis. In addition, Wwox deficiency was associated with signs of neuroinflammation such as evidence of activated microglia, astrogliosis, and overexpression of inflammatory cytokines Tnf-a and Il6. We also performed comparative transcriptome-wide expression analyses of neural stem cells grown as neurospheres from hippocampi of Wwox KO and WT mice thus identifying 283 genes significantly dysregulated in their expression. Functional annotation of transcriptome profiling differences identified ?neurological disease? and ?CNS development related functions? to be significantly enriched. Several epilepsy-related genes were found differentially expressed in Wwox KO neurospheres. This study provides the first genotype-phenotype observations as well as potential mechanistic clues associated with Wwox loss of function in the brain.
Fil: Hussain, Tabish. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Kil, Hyunsuk. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Hattiangady, Bharathi. Texas A&M Health Science Center College of Medicine; Estados Unidos
Fil: Lee, Jaeho. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Kodali, Maheedhar. Texas A&M Health Science Center College of Medicine; Estados Unidos
Fil: Shuai, Bing. Texas A&M Health Science Center College of Medicine; Estados Unidos
Fil: Attaluri, Sahithi. Texas A&M Health Science Center College of Medicine; Estados Unidos
Fil: Takata, Yoko. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Shen, Jianjun. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina
Fil: Shetty, Ashok K.. Texas A&M Health Science Center College of Medicine; Estados Unidos
Fil: Aldaz, Claudio Marcelo. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Materia
ASTROGLIOSIS
EPILEPSY
GABA-ERGIC INTERNEURONS
HIPPOCAMPUS
MICROGLIOSIS
WWOX
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/105075
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/105075
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampusHussain, TabishKil, HyunsukHattiangady, BharathiLee, JaehoKodali, MaheedharShuai, BingAttaluri, SahithiTakata, YokoShen, JianjunAbba, Martín CarlosShetty, Ashok K.Aldaz, Claudio MarceloASTROGLIOSISEPILEPSYGABA-ERGIC INTERNEURONSHIPPOCAMPUSMICROGLIOSISWWOXhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The association of WW domain-containing oxidoreductase WWOX gene loss of function with central nervous system (CNS) related pathologies is well documented. These include spinocerebellar ataxia, epilepsy and mental retardation (SCAR12, OMIM: 614322) and early infantile epileptic encephalopathy (EIEE28, OMIM: 616211) syndromes. However, there is complete lack of understanding of the pathophysiological mechanisms at play. In this study, using a Wwox knockout (Wwox KO) mouse model (2 weeks old, both sexes) and stereological studies we observe that Wwox deletion leads to a significant reduction in the number of hippocampal GABA-ergic (γ-aminobutyric acid) interneurons. Wwox KO mice displayed significantly reduced numbers of calcium-binding protein parvalbumin (PV) and neuropeptide Y (NPY) expressing interneurons in different subfields of the hippocampus in comparison to Wwox wild-type (WT) mice. We also detected decreased levels of Glutamic Acid Decarboxylase protein isoforms GAD65/67 expression in Wwox null hippocampi suggesting lower levels of GABA synthesis. In addition, Wwox deficiency was associated with signs of neuroinflammation such as evidence of activated microglia, astrogliosis, and overexpression of inflammatory cytokines Tnf-a and Il6. We also performed comparative transcriptome-wide expression analyses of neural stem cells grown as neurospheres from hippocampi of Wwox KO and WT mice thus identifying 283 genes significantly dysregulated in their expression. Functional annotation of transcriptome profiling differences identified ?neurological disease? and ?CNS development related functions? to be significantly enriched. Several epilepsy-related genes were found differentially expressed in Wwox KO neurospheres. This study provides the first genotype-phenotype observations as well as potential mechanistic clues associated with Wwox loss of function in the brain.Fil: Hussain, Tabish. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados UnidosFil: Kil, Hyunsuk. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados UnidosFil: Hattiangady, Bharathi. Texas A&M Health Science Center College of Medicine; Estados UnidosFil: Lee, Jaeho. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados UnidosFil: Kodali, Maheedhar. Texas A&M Health Science Center College of Medicine; Estados UnidosFil: Shuai, Bing. Texas A&M Health Science Center College of Medicine; Estados UnidosFil: Attaluri, Sahithi. Texas A&M Health Science Center College of Medicine; Estados UnidosFil: Takata, Yoko. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados UnidosFil: Shen, Jianjun. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados UnidosFil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Shetty, Ashok K.. Texas A&M Health Science Center College of Medicine; Estados UnidosFil: Aldaz, Claudio Marcelo. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados UnidosAcademic Press Inc Elsevier Science2019-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/105075Hussain, Tabish; Kil, Hyunsuk; Hattiangady, Bharathi; Lee, Jaeho; Kodali, Maheedhar; et al.; Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus; Academic Press Inc Elsevier Science; Neurobiology of Disease; 121; 1-2019; 163-1760969-9961CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.nbd.2018.09.026info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0969996118306612info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:35:41Zoai:ri.conicet.gov.ar:11336/105075instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 14:35:41.915CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus
title Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus
spellingShingle Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus
Hussain, Tabish
ASTROGLIOSIS
EPILEPSY
GABA-ERGIC INTERNEURONS
HIPPOCAMPUS
MICROGLIOSIS
WWOX
title_short Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus
title_full Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus
title_fullStr Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus
title_full_unstemmed Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus
title_sort Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus
dc.creator.none.fl_str_mv Hussain, Tabish
Kil, Hyunsuk
Hattiangady, Bharathi
Lee, Jaeho
Kodali, Maheedhar
Shuai, Bing
Attaluri, Sahithi
Takata, Yoko
Shen, Jianjun
Abba, Martín Carlos
Shetty, Ashok K.
Aldaz, Claudio Marcelo
author Hussain, Tabish
author_facet Hussain, Tabish
Kil, Hyunsuk
Hattiangady, Bharathi
Lee, Jaeho
Kodali, Maheedhar
Shuai, Bing
Attaluri, Sahithi
Takata, Yoko
Shen, Jianjun
Abba, Martín Carlos
Shetty, Ashok K.
Aldaz, Claudio Marcelo
author_role author
author2 Kil, Hyunsuk
Hattiangady, Bharathi
Lee, Jaeho
Kodali, Maheedhar
Shuai, Bing
Attaluri, Sahithi
Takata, Yoko
Shen, Jianjun
Abba, Martín Carlos
Shetty, Ashok K.
Aldaz, Claudio Marcelo
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ASTROGLIOSIS
EPILEPSY
GABA-ERGIC INTERNEURONS
HIPPOCAMPUS
MICROGLIOSIS
WWOX
topic ASTROGLIOSIS
EPILEPSY
GABA-ERGIC INTERNEURONS
HIPPOCAMPUS
MICROGLIOSIS
WWOX
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The association of WW domain-containing oxidoreductase WWOX gene loss of function with central nervous system (CNS) related pathologies is well documented. These include spinocerebellar ataxia, epilepsy and mental retardation (SCAR12, OMIM: 614322) and early infantile epileptic encephalopathy (EIEE28, OMIM: 616211) syndromes. However, there is complete lack of understanding of the pathophysiological mechanisms at play. In this study, using a Wwox knockout (Wwox KO) mouse model (2 weeks old, both sexes) and stereological studies we observe that Wwox deletion leads to a significant reduction in the number of hippocampal GABA-ergic (γ-aminobutyric acid) interneurons. Wwox KO mice displayed significantly reduced numbers of calcium-binding protein parvalbumin (PV) and neuropeptide Y (NPY) expressing interneurons in different subfields of the hippocampus in comparison to Wwox wild-type (WT) mice. We also detected decreased levels of Glutamic Acid Decarboxylase protein isoforms GAD65/67 expression in Wwox null hippocampi suggesting lower levels of GABA synthesis. In addition, Wwox deficiency was associated with signs of neuroinflammation such as evidence of activated microglia, astrogliosis, and overexpression of inflammatory cytokines Tnf-a and Il6. We also performed comparative transcriptome-wide expression analyses of neural stem cells grown as neurospheres from hippocampi of Wwox KO and WT mice thus identifying 283 genes significantly dysregulated in their expression. Functional annotation of transcriptome profiling differences identified ?neurological disease? and ?CNS development related functions? to be significantly enriched. Several epilepsy-related genes were found differentially expressed in Wwox KO neurospheres. This study provides the first genotype-phenotype observations as well as potential mechanistic clues associated with Wwox loss of function in the brain.
Fil: Hussain, Tabish. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Kil, Hyunsuk. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Hattiangady, Bharathi. Texas A&M Health Science Center College of Medicine; Estados Unidos
Fil: Lee, Jaeho. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Kodali, Maheedhar. Texas A&M Health Science Center College of Medicine; Estados Unidos
Fil: Shuai, Bing. Texas A&M Health Science Center College of Medicine; Estados Unidos
Fil: Attaluri, Sahithi. Texas A&M Health Science Center College of Medicine; Estados Unidos
Fil: Takata, Yoko. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Shen, Jianjun. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina
Fil: Shetty, Ashok K.. Texas A&M Health Science Center College of Medicine; Estados Unidos
Fil: Aldaz, Claudio Marcelo. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
description The association of WW domain-containing oxidoreductase WWOX gene loss of function with central nervous system (CNS) related pathologies is well documented. These include spinocerebellar ataxia, epilepsy and mental retardation (SCAR12, OMIM: 614322) and early infantile epileptic encephalopathy (EIEE28, OMIM: 616211) syndromes. However, there is complete lack of understanding of the pathophysiological mechanisms at play. In this study, using a Wwox knockout (Wwox KO) mouse model (2 weeks old, both sexes) and stereological studies we observe that Wwox deletion leads to a significant reduction in the number of hippocampal GABA-ergic (γ-aminobutyric acid) interneurons. Wwox KO mice displayed significantly reduced numbers of calcium-binding protein parvalbumin (PV) and neuropeptide Y (NPY) expressing interneurons in different subfields of the hippocampus in comparison to Wwox wild-type (WT) mice. We also detected decreased levels of Glutamic Acid Decarboxylase protein isoforms GAD65/67 expression in Wwox null hippocampi suggesting lower levels of GABA synthesis. In addition, Wwox deficiency was associated with signs of neuroinflammation such as evidence of activated microglia, astrogliosis, and overexpression of inflammatory cytokines Tnf-a and Il6. We also performed comparative transcriptome-wide expression analyses of neural stem cells grown as neurospheres from hippocampi of Wwox KO and WT mice thus identifying 283 genes significantly dysregulated in their expression. Functional annotation of transcriptome profiling differences identified ?neurological disease? and ?CNS development related functions? to be significantly enriched. Several epilepsy-related genes were found differentially expressed in Wwox KO neurospheres. This study provides the first genotype-phenotype observations as well as potential mechanistic clues associated with Wwox loss of function in the brain.
publishDate 2019
dc.date.none.fl_str_mv 2019-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/105075
Hussain, Tabish; Kil, Hyunsuk; Hattiangady, Bharathi; Lee, Jaeho; Kodali, Maheedhar; et al.; Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus; Academic Press Inc Elsevier Science; Neurobiology of Disease; 121; 1-2019; 163-176
0969-9961
CONICET Digital
CONICET
url http://hdl.handle.net/11336/105075
identifier_str_mv Hussain, Tabish; Kil, Hyunsuk; Hattiangady, Bharathi; Lee, Jaeho; Kodali, Maheedhar; et al.; Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus; Academic Press Inc Elsevier Science; Neurobiology of Disease; 121; 1-2019; 163-176
0969-9961
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.nbd.2018.09.026
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0969996118306612
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Academic Press Inc Elsevier Science
publisher.none.fl_str_mv Academic Press Inc Elsevier Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.22299

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