Excitation/inhibition balance and learning are modified by Dyrk1a gene dosage
Cognitive deficits in Down syndrome (DS) have been linked to increased synaptic inhibition, leading to an imbalance of excitation/inhibition (E/I). Various mouse models and studies from human brains have implicated an HSA21 gene, the serine/threonine kinase DYRK1A, as a candidate for inducing cognit...
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doaj-38eb53d8da744590b164b4cc0d3230c42021-03-22T12:41:14ZengElsevierNeurobiology of Disease1095-953X2014-09-01696575Excitation/inhibition balance and learning are modified by Dyrk1a gene dosageBenoit Souchet0Fayçal Guedj1Ignasi Sahún2Arnaud Duchon3Fabrice Daubigney4Anne Badel5Yuchio Yanagawa6Maria Jose Barallobre7Mara Dierssen8Eugene Yu9Yann Herault10Mariona Arbones11Nathalie Janel12Nicole Créau13Jean Maurice Delabar14Univ Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, UMR CNRS 8251, 75205 Paris, FranceUniv Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, UMR CNRS 8251, 75205 Paris, FranceGenomic Regulation Center, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona, SpainIGBMC, CNRS, INSERM, UMR7104, UMR964, Illkirch, FranceUniv Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, UMR CNRS 8251, 75205 Paris, FranceMTI, Univ Paris Diderot, Sorbonne Paris Cité, FranceDepartment of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine and JST, CREST, JapanPlataforma de Recerca Aplicada en Animal de Laboratori (PRAAL), Parc Científic de Barcelona (PCB), SpainGenomic Regulation Center, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona, SpainChildren's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USAIGBMC, CNRS, INSERM, UMR7104, UMR964, Illkirch, FranceCentro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona, Spain; Plataforma de Recerca Aplicada en Animal de Laboratori (PRAAL), Parc Científic de Barcelona (PCB), SpainUniv Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, UMR CNRS 8251, 75205 Paris, FranceUniv Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, UMR CNRS 8251, 75205 Paris, France; Corresponding authors.Univ Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, UMR CNRS 8251, 75205 Paris, France; Corresponding authors.Cognitive deficits in Down syndrome (DS) have been linked to increased synaptic inhibition, leading to an imbalance of excitation/inhibition (E/I). Various mouse models and studies from human brains have implicated an HSA21 gene, the serine/threonine kinase DYRK1A, as a candidate for inducing cognitive dysfunction. Here, consequences of alterations in Dyrk1a dosage were assessed in mouse models with varying copy numbers of Dyrk1a: mBACtgDyrk1a, Ts65Dn and Dp(16)1Yey (with 3 gene copies) and Dyrk1a(+/−) (one functional copy). Molecular (i.e. immunoblotting/immunohistochemistry) and behavioral analyses (e.g., rotarod, Morris water maze, Y-maze) were performed in mBACtgDyrk1a mice. Increased expression of DYRK1A in mBACtgDyrk1a induced molecular alterations in synaptic plasticity pathways, particularly expression changes in GABAergic and glutaminergic related proteins. Similar alterations were observed in models with partial trisomy of MMU16, Ts65Dn and Dp(16)1Yey, and were reversed in the Dyrk1a(+/−) model. Dyrk1a overexpression produced an increased number and signal intensity of GAD67 positive neurons, indicating enhanced inhibition pathways in three different models: mBACtgDyrk1a, hYACtgDyrk1a and Dp(16)1Yey. Functionally, Dyrk1a overexpression protected mice from PTZ-induced seizures related to GABAergic neuron plasticity. Our study shows that DYRK1A overexpression affects pathways involved in synaptogenesis and synaptic plasticity and influences E/I balance toward inhibition. Inhibition of DYRK1A activity offers a therapeutic target for DS, but its inhibition/activation may also be relevant for other psychiatric diseases with E/I balance alterations.http://www.sciencedirect.com/science/article/pii/S0969996114001053Down syndromeDYRK1AExcitationInhibition |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Benoit Souchet Fayçal Guedj Ignasi Sahún Arnaud Duchon Fabrice Daubigney Anne Badel Yuchio Yanagawa Maria Jose Barallobre Mara Dierssen Eugene Yu Yann Herault Mariona Arbones Nathalie Janel Nicole Créau Jean Maurice Delabar |
spellingShingle |
Benoit Souchet Fayçal Guedj Ignasi Sahún Arnaud Duchon Fabrice Daubigney Anne Badel Yuchio Yanagawa Maria Jose Barallobre Mara Dierssen Eugene Yu Yann Herault Mariona Arbones Nathalie Janel Nicole Créau Jean Maurice Delabar Excitation/inhibition balance and learning are modified by Dyrk1a gene dosage Neurobiology of Disease Down syndrome DYRK1A Excitation Inhibition |
author_facet |
Benoit Souchet Fayçal Guedj Ignasi Sahún Arnaud Duchon Fabrice Daubigney Anne Badel Yuchio Yanagawa Maria Jose Barallobre Mara Dierssen Eugene Yu Yann Herault Mariona Arbones Nathalie Janel Nicole Créau Jean Maurice Delabar |
author_sort |
Benoit Souchet |
title |
Excitation/inhibition balance and learning are modified by Dyrk1a gene dosage |
title_short |
Excitation/inhibition balance and learning are modified by Dyrk1a gene dosage |
title_full |
Excitation/inhibition balance and learning are modified by Dyrk1a gene dosage |
title_fullStr |
Excitation/inhibition balance and learning are modified by Dyrk1a gene dosage |
title_full_unstemmed |
Excitation/inhibition balance and learning are modified by Dyrk1a gene dosage |
title_sort |
excitation/inhibition balance and learning are modified by dyrk1a gene dosage |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2014-09-01 |
description |
Cognitive deficits in Down syndrome (DS) have been linked to increased synaptic inhibition, leading to an imbalance of excitation/inhibition (E/I). Various mouse models and studies from human brains have implicated an HSA21 gene, the serine/threonine kinase DYRK1A, as a candidate for inducing cognitive dysfunction. Here, consequences of alterations in Dyrk1a dosage were assessed in mouse models with varying copy numbers of Dyrk1a: mBACtgDyrk1a, Ts65Dn and Dp(16)1Yey (with 3 gene copies) and Dyrk1a(+/−) (one functional copy). Molecular (i.e. immunoblotting/immunohistochemistry) and behavioral analyses (e.g., rotarod, Morris water maze, Y-maze) were performed in mBACtgDyrk1a mice. Increased expression of DYRK1A in mBACtgDyrk1a induced molecular alterations in synaptic plasticity pathways, particularly expression changes in GABAergic and glutaminergic related proteins. Similar alterations were observed in models with partial trisomy of MMU16, Ts65Dn and Dp(16)1Yey, and were reversed in the Dyrk1a(+/−) model. Dyrk1a overexpression produced an increased number and signal intensity of GAD67 positive neurons, indicating enhanced inhibition pathways in three different models: mBACtgDyrk1a, hYACtgDyrk1a and Dp(16)1Yey. Functionally, Dyrk1a overexpression protected mice from PTZ-induced seizures related to GABAergic neuron plasticity. Our study shows that DYRK1A overexpression affects pathways involved in synaptogenesis and synaptic plasticity and influences E/I balance toward inhibition. Inhibition of DYRK1A activity offers a therapeutic target for DS, but its inhibition/activation may also be relevant for other psychiatric diseases with E/I balance alterations. |
topic |
Down syndrome DYRK1A Excitation Inhibition |
url |
http://www.sciencedirect.com/science/article/pii/S0969996114001053 |
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