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Foxp2 loss of function increases striatal direct pathway inhibition via increased GABA release
Heterozygous mutations of the Forkhead-box protein 2 (FOXP2) gene in humans cause childhood apraxia of speech. Loss of Foxp2 in mice is known to affect striatal development and impair motor skills. However, it is unknown if striatal excitatory/inhibitory balance is affected during development and if...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267273/ https://www.ncbi.nlm.nih.gov/pubmed/30187194 http://dx.doi.org/10.1007/s00429-018-1746-6 |
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author | van Rhijn, Jon-Ruben Fisher, Simon E. Vernes, Sonja C. Nadif Kasri, Nael |
author_facet | van Rhijn, Jon-Ruben Fisher, Simon E. Vernes, Sonja C. Nadif Kasri, Nael |
author_sort | van Rhijn, Jon-Ruben |
collection | PubMed |
description | Heterozygous mutations of the Forkhead-box protein 2 (FOXP2) gene in humans cause childhood apraxia of speech. Loss of Foxp2 in mice is known to affect striatal development and impair motor skills. However, it is unknown if striatal excitatory/inhibitory balance is affected during development and if the imbalance persists into adulthood. We investigated the effect of reduced Foxp2 expression, via a loss-of-function mutation, on striatal medium spiny neurons (MSNs). Our data show that heterozygous loss of Foxp2 decreases excitatory (AMPA receptor-mediated) and increases inhibitory (GABA receptor-mediated) currents in D1 dopamine receptor positive MSNs of juvenile and adult mice. Furthermore, reduced Foxp2 expression increases GAD67 expression, leading to both increased presynaptic content and release of GABA. Finally, pharmacological blockade of inhibitory activity in vivo partially rescues motor skill learning deficits in heterozygous Foxp2 mice. Our results suggest a novel role for Foxp2 in the regulation of striatal direct pathway activity through managing inhibitory drive. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00429-018-1746-6) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6267273 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-62672732018-12-11 Foxp2 loss of function increases striatal direct pathway inhibition via increased GABA release van Rhijn, Jon-Ruben Fisher, Simon E. Vernes, Sonja C. Nadif Kasri, Nael Brain Struct Funct Original Article Heterozygous mutations of the Forkhead-box protein 2 (FOXP2) gene in humans cause childhood apraxia of speech. Loss of Foxp2 in mice is known to affect striatal development and impair motor skills. However, it is unknown if striatal excitatory/inhibitory balance is affected during development and if the imbalance persists into adulthood. We investigated the effect of reduced Foxp2 expression, via a loss-of-function mutation, on striatal medium spiny neurons (MSNs). Our data show that heterozygous loss of Foxp2 decreases excitatory (AMPA receptor-mediated) and increases inhibitory (GABA receptor-mediated) currents in D1 dopamine receptor positive MSNs of juvenile and adult mice. Furthermore, reduced Foxp2 expression increases GAD67 expression, leading to both increased presynaptic content and release of GABA. Finally, pharmacological blockade of inhibitory activity in vivo partially rescues motor skill learning deficits in heterozygous Foxp2 mice. Our results suggest a novel role for Foxp2 in the regulation of striatal direct pathway activity through managing inhibitory drive. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00429-018-1746-6) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2018-09-05 2018 /pmc/articles/PMC6267273/ /pubmed/30187194 http://dx.doi.org/10.1007/s00429-018-1746-6 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Original Article van Rhijn, Jon-Ruben Fisher, Simon E. Vernes, Sonja C. Nadif Kasri, Nael Foxp2 loss of function increases striatal direct pathway inhibition via increased GABA release |
title | Foxp2 loss of function increases striatal direct pathway inhibition via increased GABA release |
title_full | Foxp2 loss of function increases striatal direct pathway inhibition via increased GABA release |
title_fullStr | Foxp2 loss of function increases striatal direct pathway inhibition via increased GABA release |
title_full_unstemmed | Foxp2 loss of function increases striatal direct pathway inhibition via increased GABA release |
title_short | Foxp2 loss of function increases striatal direct pathway inhibition via increased GABA release |
title_sort | foxp2 loss of function increases striatal direct pathway inhibition via increased gaba release |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267273/ https://www.ncbi.nlm.nih.gov/pubmed/30187194 http://dx.doi.org/10.1007/s00429-018-1746-6 |
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