title: Overexpression of Dyrk1A, a Down Syndrome Candidate, Decreases Excitability and Impairs Gamma Oscillations in the Prefrontal Cortex.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Systems Neuroscience, August Pi i Sunyer Biomedical research Institute (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Marcel
authors.identifier: http://orcid.org/0000-0003-0373-1725
authors.initials: M
authors.lastname: Ruiz-Mejias
authors.affiliation: Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, 08003 Barcelona, Spain, Pompeu Fabra University (UPF), 08003 Barcelona, Spain, Centre for Biomedical Research on Rare Diseases (CIBERER) 08003 Barcelona, Spain.
authors.forename: Maria
authors.identifier: http://orcid.org/0000-0002-0836-6491
authors.initials: M
authors.lastname: Martinez de Lagran
authors.affiliation: National Institute of Health, 00161 Rome, Italy.
authors.forename: Maurizio
authors.identifier: http://orcid.org/0000-0002-2356-4509
authors.initials: M
authors.lastname: Mattia
authors.affiliation: Systems Neuroscience, August Pi i Sunyer Biomedical research Institute (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Patricia
authors.identifier: http://orcid.org/0000-0002-3238-4497
authors.initials: P
authors.lastname: Castano-Prat
authors.affiliation: Systems Neuroscience, August Pi i Sunyer Biomedical research Institute (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Lorena
authors.identifier: http://orcid.org/0000-0002-5205-5076
authors.initials: L
authors.lastname: Perez-Mendez
authors.affiliation: Systems Neuroscience, August Pi i Sunyer Biomedical research Institute (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Ciria-Suarez
authors.affiliation: Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, 08003 Barcelona, Spain, Pompeu Fabra University (UPF), 08003 Barcelona, Spain, Centre for Biomedical Research on Rare Diseases (CIBERER) 08003 Barcelona, Spain.
authors.forename: Thomas
authors.identifier: http://orcid.org/0000-0001-9209-9228
authors.initials: T
authors.lastname: Gener
authors.affiliation: Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, 08003 Barcelona, Spain, Pompeu Fabra University (UPF), 08003 Barcelona, Spain, Centre for Biomedical Research on Rare Diseases (CIBERER) 08003 Barcelona, Spain.
authors.forename: Belen
authors.initials: B
authors.lastname: Sancristobal
authors.affiliation: Pompeu Fabra University (UPF), 08003 Barcelona, Spain.
authors.forename: Jordi
authors.identifier: http://orcid.org/0000-0002-3716-7520
authors.initials: J
authors.lastname: García-Ojalvo
authors.affiliation: Neuroscience Department, Pablo de Olavide University 41013 Seville, Spain, and.
authors.forename: Agnès
authors.initials: A
authors.lastname: Gruart
authors.affiliation: Neuroscience Department, Pablo de Olavide University 41013 Seville, Spain, and.
authors.forename: José M
authors.identifier: http://orcid.org/0000-0001-7369-4195
authors.initials: JM
authors.lastname: Delgado-García
authors.affiliation: Systems Neuroscience, August Pi i Sunyer Biomedical research Institute (IDIBAPS), 08036 Barcelona, Spain, Catalan Institution for Research and Advanced Studies (ICREA) 08010 Barcelona, Spain mara.dierssen@crg.eu msanche3@clinic.ub.es.
authors.forename: Maria V
authors.identifier: http://orcid.org/0000-0002-8437-9083
authors.initials: MV
authors.lastname: Sanchez-Vives
authors.affiliation: Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, 08003 Barcelona, Spain, Pompeu Fabra University (UPF), 08003 Barcelona, Spain, Centre for Biomedical Research on Rare Diseases (CIBERER) 08003 Barcelona, Spain, mara.dierssen@crg.eu msanche3@clinic.ub.es.
authors.forename: Mara
authors.identifier: http://orcid.org/0000-0003-0853-6865
authors.initials: M
authors.lastname: Dierssen
mesh_terms: D000200:Action Potentials / Q000235:genetics / Q000502:physiology*; D000818:Animals; D003198:Computer Simulation; D050485:GABA Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D065818:Gamma Rhythm / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008959:Models, Neurological; D009474:Neurons / Q000502:physiology*; D010320:Parvalbumins / Q000378:metabolism; D017397:Prefrontal Cortex / Q000166:cytology / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D013004:Somatostatin / Q000378:metabolism; D013057:Spectrum Analysis; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism; D014851:Wakefulness; D000097603:Dyrk Kinases
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; D008164:Luminescent Proteins; D010320:Parvalbumins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D013004:Somatostatin; D050598:Vesicular Glutamate Transport Protein 1; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; D000097603:Dyrk Kinases; C493465:Slc17a7 protein, mouse; C492244:Viaat protein, mouse
keywords: DYRK1A; Down syndrome; gamma oscillations; prefrontal cortex; transgenic mouse model