Overexpression of Dyrk1A, a down syndrome candidate, decreases excitability and impairs gamma oscillations in the prefrontal cortex

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• dc.contributor.author Ruiz Mejias, Marcelca
• dc.contributor.author Martínez de Lagrán Cabredo, Maríaca
• dc.contributor.author Mattia, Maurizioca
• dc.contributor.author Castaño Prat, Patriciaca
• dc.contributor.author Pérez Mendez, Lorenaca
• dc.contributor.author Ciria Suarez, Lauraca
• dc.contributor.author Gener, Thomasca
• dc.contributor.author Sancristóbal, Belenca
• dc.contributor.author García Ojalvo, Jordica
• dc.contributor.author Gruart, Agnèsca
• dc.contributor.author Delgado García, José Maríaca
• dc.contributor.author Sanchez-Vives, Maria V.ca
• dc.contributor.author Dierssen, Maraca
• dc.date.accessioned 2016-04-06T16:55:02Z
• dc.date.available 2016-09-30T02:00:05Z
• dc.date.issued 2016
• dc.description.abstract The dual-specificity tyrosine phosphorylation-regulated kinase DYRK1A is a serine/threonine kinase involved in neuronal differentiation and synaptic plasticity and a major candidate of Down syndrome brain alterations and cognitive deficits. DYRK1A is strongly expressed in the cerebral cortex, and its overexpression leads to defective cortical pyramidal cell morphology, synaptic plasticity deficits, and altered excitation/inhibition balance. These previous observations, however, do not allow predicting how the behavior of the prefrontal cortex (PFC) network and the resulting properties of its emergent activity are affected. Here, we integrate functional, anatomical, and computational data describing the prefrontal network alterations in transgenic mice overexpressingDyrk1A(TgDyrk1A). Usingin vivoextracellular recordings, we show decreased firing rate and gamma frequency power in the prefrontal network of anesthetized and awakeTgDyrk1Amice. Immunohistochemical analysis identified a selective reduction of vesicular GABA transporter punctae on parvalbumin positive neurons, without changes in the number of cortical GABAergic neurons in the PFC ofTgDyrk1Amice, which suggests that selective disinhibition of parvalbumin interneurons would result in an overinhibited functional network. Using a conductance-based computational model, we quantitatively demonstrate that this alteration could explain the observed functional deficits including decreased gamma power and firing rate. Our results suggest that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of Down syndrome. SIGNIFICANCE STATEMENT:DYRK1Ais a major candidate gene in Down syndrome. Its overexpression results into altered cognitive abilities, explained by defective cortical microarchitecture and excitation/inhibition imbalance. An open question is how these deficits impact the functionality of the prefrontal cortex network. Combining functional, anatomical, and computational approaches, we identified decreased neuronal firing rate and deficits in gamma frequency in the prefrontal cortices of transgenic mice overexpressingDyrk1A We also identified a reduction of vesicular GABA transporter punctae specifically on parvalbumin positive interneurons. Using a conductance-based computational model, we demonstrate that this decreased inhibition on interneurons recapitulates the observed functional deficits, including decreased gamma power and firing rate. Our results suggest that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of Down syndrome.ca
• dc.description.sponsorship This work was supported by Foundation Jerome Lejeune Grant 937-SM2011B, Ministerio de Ciencia e Innovación Grants BFU2011-27094 and BFU2014-52467-R, and the EU PF7 FET CORTICONIC contract 600806 (M.V.S.-V.); Ministerio de Economia y Competitividad Grant FIS2012-37655 and the Institució Catalana de Recerca i Estudis Avançats Academia (J.G.O.); and the FRAXA Foundation, Fondation Jerome Lejeune Grant 937-SM2011B, Ministerio de Economia y Competitividad Grants SAF2013-49129-C2-1-R and “Centro de Excelencia Severo Ochoa 2013–2017” SEV-2012-0208, EU ERA-Net Neuron (FOOD for THOUGHT), Secretaria de Universidades e Investigación del Departamento de Economía y Conocimiento de la Generalidad de Cataluña Grant SGR 2014/1125, and CIBERER (Centro de Investigación Biomédica en Red de Enfermedades Raras) (M.D.).
• dc.format.mimetype application/pdfca
• dc.identifier.citation Ruiz-Mejias M, Martinez de Lagran M, Mattia M, Castano-Prat P, Perez-Mendez L, Ciria-Suarez L et al. Overexpression of Dyrk1A, a down syndrome candidate, decreases excitability and impairs gamma oscillations in the prefrontal cortex. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2016; 36(13): 3648-3659. DOI 10.1523/JNEUROSCI.2517-15.2016ca
• dc.identifier.doi http://dx.doi.org/10.1523/JNEUROSCI.2517-15.2016
• dc.identifier.issn 0270-6474
• dc.identifier.uri http://hdl.handle.net/10230/26049
• dc.language.iso engca
• dc.publisher Society for Neuroscienceca
• dc.relation.ispartof The Journal of neuroscience: the official journal of the Society for Neuroscience. 2016; 36(13): 3648-3659
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2013-49129-C2-1-R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BFU2011-27094
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2014-52467-R
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/600806
• dc.rights © The Authors. Published by the Society for Neuroscience http://www.jneurosci.org/content/36/13/3648.long. The work is published under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, as described at https://creativecommons.org/licenses/by/4.0/ca
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/ca
• dc.subject.keyword DYRK1A
• dc.subject.keyword Down syndrome
• dc.subject.keyword Gamma oscillations
• dc.subject.keyword Prefrontal cortex
• dc.subject.keyword Transgenic mouse model
• dc.subject.other Down, Síndrome de -- Models animalsca
• dc.subject.other Còrtex cerebralca
• dc.title Overexpression of Dyrk1A, a down syndrome candidate, decreases excitability and impairs gamma oscillations in the prefrontal cortexca
• dc.type info:eu-repo/semantics/articleca
• dc.type.version info:eu-repo/semantics/publishedVersionca