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Pharmacological correction of excitation/inhibition imbalance in Down syndrome mouse models

By Benoit Souchet, Fayçal Guedj, Zsuza Penke-Verdier, Fabrice Daubigney, Arnaud Duchon, Yann Herault, Jean-Charles Bizot, Nathalie Janel, Nicole Créau, Benoit Delatour and Jean M. Delabar

Abstract

International audienceCognitive 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

Topics: Down syndrome, DYRK1A, EGCG, GABA pathway, glutamate pathway, excitation/inhibition balance, [ SDV.SP ] Life Sciences [q-bio]/Pharmaceutical sciences
Publisher: Frontiers
Year: 2015
DOI identifier: 10.3389/fnbeh.2015.00267
OAI identifier: oai:HAL:hal-01263753v1
Provided by: Hal-Diderot

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