<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
- Institución
- Universidad Nacional de La Plata
- OAI Identificador
- oai:sedici.unlp.edu.ar:10915/124879
Ver los metadatos del registro completo
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<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 Articulo 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://sedici.unlp.edu.ar/handle/10915/124879 |
url |
http://sedici.unlp.edu.ar/handle/10915/124879 |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/issn/1095-953X 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 http://creativecommons.org/licenses/by-nc-nd/4.0/ 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 163-176 |
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SEDICI (UNLP) - Universidad Nacional de La Plata |
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