Overexpression of Dyrk1A, a Down Syndrome Candidate, Decreases Excitability and Impairs Gamma Oscillations in the Prefrontal Cortex.
Marcel Ruiz-MejiasMaría Martínez de LagránMaurizio MattiaPatricia Castano-PratLorena Perez-MendezLaura Ciria-SuarezThomas GenerBelen SancristobalJordi García-OjalvoAgnès GruartJosé María Delgado-GarcíaMaria V Sanchez-VivesMara DierssenPublished in: The Journal of neuroscience : the official journal of the Society for Neuroscience (2016)
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.