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J Neurosci. 2016 Mar 30;36(13):3648-59. doi: 10.1523/JNEUROSCI.2517-15.2016.

Overexpression of Dyrk1A, a Down Syndrome Candidate, Decreases Excitability and Impairs Gamma Oscillations in the Prefrontal Cortex.

Author information

1
Systems Neuroscience, August Pi i Sunyer Biomedical research Institute (IDIBAPS), 08036 Barcelona, Spain.
2
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.
3
National Institute of Health, 00161 Rome, Italy.
4
Pompeu Fabra University (UPF), 08003 Barcelona, Spain.
5
Neuroscience Department, Pablo de Olavide University 41013 Seville, Spain, and.
6
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.
7
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.

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.

KEYWORDS:

DYRK1A; Down syndrome; gamma oscillations; prefrontal cortex; transgenic mouse model

PMID:
27030752
DOI:
10.1523/JNEUROSCI.2517-15.2016
[Indexed for MEDLINE]
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