title: Excitation/inhibition balance and learning are modified by Dyrk1a gene dosage.
abstract: Cognitive deficits in Down syndrome (DS) have been linked to increased synaptic inhibition, leading to an imbalance of excitation/inhibition (E/I). Various mouse models and studies from human brains have implicated an HSA21 gene, the serine/threonine kinase DYRK1A, as a candidate for inducing cognitive dysfunction. Here, consequences of alterations in Dyrk1a dosage were assessed in mouse models with varying copy numbers of Dyrk1a: mBACtgDyrk1a, Ts65Dn and Dp(16)1Yey (with 3 gene copies) and Dyrk1a(+/-) (one functional copy). Molecular (i.e. immunoblotting/immunohistochemistry) and behavioral analyses (e.g., rotarod, Morris water maze, Y-maze) were performed in mBACtgDyrk1a mice. Increased expression of DYRK1A in mBACtgDyrk1a induced molecular alterations in synaptic plasticity pathways, particularly expression changes in GABAergic and glutaminergic related proteins. Similar alterations were observed in models with partial trisomy of MMU16, Ts65Dn and Dp(16)1Yey, and were reversed in the Dyrk1a(+/-) model. Dyrk1a overexpression produced an increased number and signal intensity of GAD67 positive neurons, indicating enhanced inhibition pathways in three different models: mBACtgDyrk1a, hYACtgDyrk1a and Dp(16)1Yey. Functionally, Dyrk1a overexpression protected mice from PTZ-induced seizures related to GABAergic neuron plasticity. Our study shows that DYRK1A overexpression affects pathways involved in synaptogenesis and synaptic plasticity and influences E/I balance toward inhibition. Inhibition of DYRK1A activity offers a therapeutic target for DS, but its inhibition/activation may also be relevant for other psychiatric diseases with E/I balance alterations.
authors.affiliation: Univ Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, UMR CNRS 8251, 75205 Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Souchet
authors.affiliation: Univ Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, UMR CNRS 8251, 75205 Paris, France.
authors.forename: Fayçal
authors.initials: F
authors.lastname: Guedj
authors.affiliation: Genomic Regulation Center, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona, Spain.
authors.forename: Ignasi
authors.initials: I
authors.lastname: Sahún
authors.affiliation: IGBMC, CNRS, INSERM, UMR7104, UMR964, Illkirch, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Duchon
authors.affiliation: Univ Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, UMR CNRS 8251, 75205 Paris, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Daubigney
authors.affiliation: MTI, Univ Paris Diderot, Sorbonne Paris Cité, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Badel
authors.affiliation: Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine and JST, CREST, Japan.
authors.forename: Yuchio
authors.initials: Y
authors.lastname: Yanagawa
authors.affiliation: Plataforma de Recerca Aplicada en Animal de Laboratori (PRAAL), Parc Científic de Barcelona (PCB), Spain.
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Barallobre
authors.affiliation: Genomic Regulation Center, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona, Spain.
authors.forename: Mara
authors.initials: M
authors.lastname: Dierssen
authors.affiliation: Children's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Yu
authors.affiliation: IGBMC, CNRS, INSERM, UMR7104, UMR964, Illkirch, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Herault
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona, Spain; Plataforma de Recerca Aplicada en Animal de Laboratori (PRAAL), Parc Científic de Barcelona (PCB), Spain.
authors.forename: Mariona
authors.initials: M
authors.lastname: Arbones
authors.affiliation: Univ Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, UMR CNRS 8251, 75205 Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Janel
authors.affiliation: Univ Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, UMR CNRS 8251, 75205 Paris, France. Electronic address: creau@univ-paris-diderot.fr.
authors.forename: Nicole
authors.initials: N
authors.lastname: Créau
authors.affiliation: Univ Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, UMR CNRS 8251, 75205 Paris, France. Electronic address: delabar@univ-paris-diderot.fr.
authors.forename: Jean Maurice
authors.initials: JM
authors.lastname: Delabar
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics / Q000503:physiopathology / Q000523:psychology; D018628:Gene Dosage; D006801:Humans; D007858:Learning / Q000502:physiology; D008297:Male; D008568:Memory / Q000502:physiology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D009433:Neural Inhibition / Q000235:genetics* / Q000502:physiology; D009473:Neuronal Plasticity / Q000235:genetics* / Q000502:physiology; D009474:Neurons / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D012640:Seizures / Q000235:genetics / Q000503:physiopathology; D013569:Synapses / Q000235:genetics / Q000502:physiology; D000097603:Dyrk Kinases
chemical_list: D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases
keywords: DYRK1A; Down syndrome; Excitation; Inhibition