<i>Wwox</i> 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, C. 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.
Facultad de Ciencias Médicas
Centro de Investigaciones Inmunológicas Básicas y Aplicadas
Materia
Medicina
Wwox
Epilepsy
Hippocampus
GABA-ergic interneurons
Microgliosis
Astrogliosis
Nivel de accesibilidad
acceso abierto
Condiciones de uso
http://creativecommons.org/licenses/by-nc-nd/4.0/
Repositorio
SEDICI (UNLP)
Institución
Universidad Nacional de La Plata
OAI Identificador
oai:sedici.unlp.edu.ar:10915/124879

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network_name_str SEDICI (UNLP)
spelling <i>Wwox</i> 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, C. MarceloMedicinaWwoxEpilepsyHippocampusGABA-ergic interneuronsMicrogliosisAstrogliosisThe association of WW domain-containing oxidoreductase <i>WWOX</i> 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 <i>Wwox</i> knockout (<i>Wwox KO</i>) mouse model (2 weeks old, both sexes) and stereological studies we observe that <i>Wwox</i> deletion leads to a significant reduction in the number of hippocampal GABA-ergic (γ-aminobutyric acid) interneurons. <i>Wwox KO</i> 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 <i>Wwox</i> wild-type (<i>WT</i>) mice. We also detected decreased levels of Glutamic Acid Decarboxylase protein isoforms GAD65/67 expression in <i>Wwox</i> null hippocampi suggesting lower levels of GABA synthesis. In addition, <i>Wwox</i> deficiency was associated with signs of neuroinflammation such as evidence of activated microglia, astrogliosis, and overexpression of inflammatory cytokines <i>Tnf-a</i> and <i>Il6</i>. We also performed comparative transcriptome-wide expression analyses of neural stem cells grown as neurospheres from hippocampi of <i>Wwox KO</i> and <i>WT</i> 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 <i>Wwox KO</i> neurospheres. This study provides the first genotype-phenotype observations as well as potential mechanistic clues associated with <i>Wwox</i> loss of function in the brain.Facultad de Ciencias MédicasCentro de Investigaciones Inmunológicas Básicas y Aplicadas2019-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionArticulohttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdf163-176http://sedici.unlp.edu.ar/handle/10915/124879enginfo:eu-repo/semantics/altIdentifier/issn/1095-953Xinfo:eu-repo/semantics/altIdentifier/issn/0969-9961info:eu-repo/semantics/altIdentifier/pmid/30290271info:eu-repo/semantics/altIdentifier/doi/10.1016/j.nbd.2018.09.026info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc-nd/4.0/Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)reponame:SEDICI (UNLP)instname:Universidad Nacional de La Platainstacron:UNLP2025-09-29T11:29:48Zoai:sedici.unlp.edu.ar:10915/124879Institucionalhttp://sedici.unlp.edu.ar/Universidad públicaNo correspondehttp://sedici.unlp.edu.ar/oai/snrdalira@sedici.unlp.edu.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:13292025-09-29 11:29:48.475SEDICI (UNLP) - Universidad Nacional de La Platafalse
dc.title.none.fl_str_mv <i>Wwox</i> deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus
title <i>Wwox</i> deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus
spellingShingle <i>Wwox</i> deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus
Hussain, Tabish
Medicina
Wwox
Epilepsy
Hippocampus
GABA-ergic interneurons
Microgliosis
Astrogliosis
title_short <i>Wwox</i> deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus
title_full <i>Wwox</i> deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus
title_fullStr <i>Wwox</i> deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus
title_full_unstemmed <i>Wwox</i> deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus
title_sort <i>Wwox</i> 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, C. 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, C. 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, C. Marcelo
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Medicina
Wwox
Epilepsy
Hippocampus
GABA-ergic interneurons
Microgliosis
Astrogliosis
topic Medicina
Wwox
Epilepsy
Hippocampus
GABA-ergic interneurons
Microgliosis
Astrogliosis
dc.description.none.fl_txt_mv The association of WW domain-containing oxidoreductase <i>WWOX</i> 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 <i>Wwox</i> knockout (<i>Wwox KO</i>) mouse model (2 weeks old, both sexes) and stereological studies we observe that <i>Wwox</i> deletion leads to a significant reduction in the number of hippocampal GABA-ergic (γ-aminobutyric acid) interneurons. <i>Wwox KO</i> 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 <i>Wwox</i> wild-type (<i>WT</i>) mice. We also detected decreased levels of Glutamic Acid Decarboxylase protein isoforms GAD65/67 expression in <i>Wwox</i> null hippocampi suggesting lower levels of GABA synthesis. In addition, <i>Wwox</i> deficiency was associated with signs of neuroinflammation such as evidence of activated microglia, astrogliosis, and overexpression of inflammatory cytokines <i>Tnf-a</i> and <i>Il6</i>. We also performed comparative transcriptome-wide expression analyses of neural stem cells grown as neurospheres from hippocampi of <i>Wwox KO</i> and <i>WT</i> 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 <i>Wwox KO</i> neurospheres. This study provides the first genotype-phenotype observations as well as potential mechanistic clues associated with <i>Wwox</i> loss of function in the brain.
Facultad de Ciencias Médicas
Centro de Investigaciones Inmunológicas Básicas y Aplicadas
description The association of WW domain-containing oxidoreductase <i>WWOX</i> 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 <i>Wwox</i> knockout (<i>Wwox KO</i>) mouse model (2 weeks old, both sexes) and stereological studies we observe that <i>Wwox</i> deletion leads to a significant reduction in the number of hippocampal GABA-ergic (γ-aminobutyric acid) interneurons. <i>Wwox KO</i> 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 <i>Wwox</i> wild-type (<i>WT</i>) mice. We also detected decreased levels of Glutamic Acid Decarboxylase protein isoforms GAD65/67 expression in <i>Wwox</i> null hippocampi suggesting lower levels of GABA synthesis. In addition, <i>Wwox</i> deficiency was associated with signs of neuroinflammation such as evidence of activated microglia, astrogliosis, and overexpression of inflammatory cytokines <i>Tnf-a</i> and <i>Il6</i>. We also performed comparative transcriptome-wide expression analyses of neural stem cells grown as neurospheres from hippocampi of <i>Wwox KO</i> and <i>WT</i> 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 <i>Wwox KO</i> neurospheres. This study provides the first genotype-phenotype observations as well as potential mechanistic clues associated with <i>Wwox</i> 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
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status_str publishedVersion
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url http://sedici.unlp.edu.ar/handle/10915/124879
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language eng
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info:eu-repo/semantics/altIdentifier/issn/0969-9961
info:eu-repo/semantics/altIdentifier/pmid/30290271
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.nbd.2018.09.026
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
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Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
dc.format.none.fl_str_mv application/pdf
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