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

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 en...

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Autores principales: 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
Formato: Articulo
Lenguaje:Inglés
Publicado: 2019
Materias:
Medicina
Wwox
Epilepsy
Hippocampus
GABA-ergic interneurons
Microgliosis
Astrogliosis
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/124879
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-124879
record_format dspace
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Inglés
topic Medicina
Wwox
Epilepsy
Hippocampus
GABA-ergic interneurons
Microgliosis
Astrogliosis
spellingShingle Medicina
Wwox
Epilepsy
Hippocampus
GABA-ergic interneurons
Microgliosis
Astrogliosis
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
<i>Wwox</i> deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus
topic_facet Medicina
Wwox
Epilepsy
Hippocampus
GABA-ergic interneurons
Microgliosis
Astrogliosis
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.
format Articulo
Articulo
author 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_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_sort Hussain, Tabish
title <i>Wwox</i> deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus
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
publishDate 2019
url http://sedici.unlp.edu.ar/handle/10915/124879
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