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Sci Rep. 2019 Mar 8;9(1):3914. doi: 10.1038/s41598-019-40328-9.

Prenatal treatment with EGCG enriched green tea extract rescues GAD67 related developmental and cognitive defects in Down syndrome mouse models.

Souchet B1, Duchon A2,3,4,5,6, Gu Y1, Dairou J7, Chevalier C2,3,4,5,6, Daubigney F1, Nalesso V2,3,4,5,6, Créau N1, Yu Y8, Janel N1,8, Herault Y9,10,11,12,13, Delabar JM14,15,16.

Author information

1
Université Paris-Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, National Centre for Scientific Research (CNRS), UMR 8251, Paris, France.
2
Institut Génétique Biologie Moléculaire Cellulaire, CNRS, French National Institute of Health and Medical Research (INSERM), UMR 7104, UMR 964, Illkirch, France.
3
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, 1 rue Laurent Fries, 67404, Illkirch, France.
4
CNRS, UMR 7104, Illkirch, France.
5
INSERM, U964, Illkirch, France.
6
Université de Strasbourg, 1 rue Laurent Fries, 67404, Illkirch, France.
7
CNRS, UMR 8601, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université Paris Descartes-Sorbonne Paris Cité, 75270, Paris, France.
8
Children's Guild Foundation Down Syndrome Research Program, Department of Cancer Genetics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
9
Institut Génétique Biologie Moléculaire Cellulaire, CNRS, French National Institute of Health and Medical Research (INSERM), UMR 7104, UMR 964, Illkirch, France. Herault@igbmc.fr.
10
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, 1 rue Laurent Fries, 67404, Illkirch, France. Herault@igbmc.fr.
11
CNRS, UMR 7104, Illkirch, France. Herault@igbmc.fr.
12
INSERM, U964, Illkirch, France. Herault@igbmc.fr.
13
Université de Strasbourg, 1 rue Laurent Fries, 67404, Illkirch, France. Herault@igbmc.fr.
14
Université Paris-Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, National Centre for Scientific Research (CNRS), UMR 8251, Paris, France. jeanmaurice.delabar@icm-institute.org.
15
INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et la Moelle épinière, ICM, Paris, France. jeanmaurice.delabar@icm-institute.org.
16
Brain & Spine Institute (ICM) CNRS UMR7225, Inserm UMRS 975, Paris, France. jeanmaurice.delabar@icm-institute.org.

Abstract

Down syndrome is a common genetic disorder caused by trisomy of chromosome 21. Brain development in affected foetuses might be improved through prenatal treatment. One potential target is DYRK1A, a multifunctional kinase encoded by chromosome 21 that, when overexpressed, alters neuronal excitation-inhibition balance and increases GAD67 interneuron density. We used a green tea extract enriched in EGCG to inhibit DYRK1A function only during gestation of transgenic mice overexpressing Dyrk1a (mBACtgDyrk1a). Adult mice treated prenatally displayed reduced levels of inhibitory markers, restored VGAT1/VGLUT1 balance, and rescued density of GAD67 interneurons. Similar results for gabaergic and glutamatergic markers and interneuron density were obtained in Dp(16)1Yey mice, trisomic for 140 chromosome 21 orthologs; thus, prenatal EGCG exhibits efficacy in a more complex DS model. Finally, cognitive and behaviour testing showed that adult Dp(16)1Yey mice treated prenatally had improved novel object recognition memory but do not show improvement with Y maze paradigm. These findings provide empirical support for a prenatal intervention that targets specific neural circuitries.

PMID:
30850713
DOI:
10.1038/s41598-019-40328-9
Free PMC Article

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