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.

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.).