title: Pharmacological correction of excitation/inhibition imbalance in Down syndrome mouse models.
abstract: Cognitive impairment in Down syndrome (DS) has been linked to increased synaptic inhibition. The underlying mechanisms remain unknown, but memory deficits are rescued in DS mouse models by drugs targeting GABA receptors. Similarly, administration of epigallocatechin gallate (EGCG)-containing extracts rescues cognitive phenotypes in Ts65Dn mice, potentially through GABA pathway. Some developmental and cognitive alterations have been traced to increased expression of the serine-threonine kinase DYRK1A on Hsa21. To better understand excitation/inhibition balance in DS, we investigated the consequences of long-term (1-month) treatment with EGCG-containing extracts in adult mBACtgDyrk1a mice that overexpress Dyrk1a. Administration of POL60 rescued components of GABAergic and glutamatergic pathways in cortex and hippocampus but not cerebellum. An intermediate dose (60 mg/kg) of decaffeinated green tea extract (MGTE) acted on components of both GABAergic and glutamatergic pathways and rescued behavioral deficits as demonstrated on the alternating paradigm, but did not rescue protein level of GABA-synthesizing GAD67. These results indicate that excessive synaptic inhibition in people with DS may be attributable, in large part, to increased DYRK1A dosage. Thus, controlling the level of active DYRK1A is a clear issue for DS therapy. This study also defines a panel of synaptic markers for further characterization of DS treatments in murine models.
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, UMR Centre National de la Recherche Scientifique 8251 Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Souchet
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, UMR Centre National de la Recherche Scientifique 8251 Paris, France ; Tufts Medical Center, Mother Infant Research Institute Boston, MA, USA.
authors.forename: Fayçal
authors.initials: F
authors.lastname: Guedj
authors.affiliation: Université Pierre-et-Marie-Curie Paris, 06 UMR S 1127, Centre National de la Recherche Scientifique UMR 7225, Institut National de la Santé et de la Recherche Médicale, U 1127, Sorbonne Universités, Institut du Cerveau et de la Moelle Epiniere Paris, France.
authors.forename: Zsuza
authors.initials: Z
authors.lastname: Penke-Verdier
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, UMR Centre National de la Recherche Scientifique 8251 Paris, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Daubigney
authors.affiliation: Institut Génétique Biologie Moléculaire Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, UMR7104, UMR964 Illkirch, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Duchon
authors.affiliation: Institut Génétique Biologie Moléculaire Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, UMR7104, UMR964 Illkirch, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Herault
authors.affiliation: Key-Obs Orléans, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Bizot
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, UMR Centre National de la Recherche Scientifique 8251 Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Janel
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, UMR Centre National de la Recherche Scientifique 8251 Paris, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Créau
authors.affiliation: Université Pierre-et-Marie-Curie Paris, 06 UMR S 1127, Centre National de la Recherche Scientifique UMR 7225, Institut National de la Santé et de la Recherche Médicale, U 1127, Sorbonne Universités, Institut du Cerveau et de la Moelle Epiniere Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Delatour
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, UMR Centre National de la Recherche Scientifique 8251 Paris, France ; Université Pierre-et-Marie-Curie Paris, 06 UMR S 1127, Centre National de la Recherche Scientifique UMR 7225, Institut National de la Santé et de la Recherche Médicale, U 1127, Sorbonne Universités, Institut du Cerveau et de la Moelle Epiniere Paris, France.
authors.forename: Jean M
authors.initials: JM
authors.lastname: Delabar
keywords: DYRK1A; Down syndrome; EGCG; GABA pathway; excitation/inhibition balance; glutamate pathway