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Nat Commun. 2018 Oct 15;9(1):4272. doi: 10.1038/s41467-018-06675-3.

Modulation of AMPA receptor surface diffusion restores hippocampal plasticity and memory in Huntington's disease models.

Author information

1
Interdisciplinary Institute for Neuroscience, University of Bordeaux, Bordeaux, 33076, France. hongyu.zhang@uib.no.
2
Interdisciplinary Institute for Neuroscience, Centre National de la Recherche Scientifique (CNRS) UMR 5297, Bordeaux, 33076, France. hongyu.zhang@uib.no.
3
Department of Biomedicine, KG Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Jonas Lies vei 91, N-5009, Bergen, Norway. hongyu.zhang@uib.no.
4
Interdisciplinary Institute for Neuroscience, University of Bordeaux, Bordeaux, 33076, France.
5
Interdisciplinary Institute for Neuroscience, Centre National de la Recherche Scientifique (CNRS) UMR 5297, Bordeaux, 33076, France.
6
Institut Curie, CNRS, UMR3306, Inserm, U1005, F-91405, Orsay, France.
7
INSERM U894, Center of Psychiatry and Neuroscience, Paris, France, University Paris-Descartes, Paris, 75006, France.
8
Univ. Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, F-38000, Grenoble, France.
9
INSERM, U1216, F-38000, Grenoble, France.
10
Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, University of Bordeaux, Bordeaux, 33000, France.
11
Université Paris-Saclay, Univ. Paris-Sud, Faculté de Pharmacie, CESP, INSERM UMRS1178, Chatenay-Malabry, 92296, France.
12
Univ. Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, F-38000, Grenoble, France. frederic.saudou@inserm.fr.
13
INSERM, U1216, F-38000, Grenoble, France. frederic.saudou@inserm.fr.
14
CHU Grenoble Alpes, F-38000, Grenoble, France. frederic.saudou@inserm.fr.
15
Interdisciplinary Institute for Neuroscience, University of Bordeaux, Bordeaux, 33076, France. daniel.choquet@u-bordeaux.fr.
16
Interdisciplinary Institute for Neuroscience, Centre National de la Recherche Scientifique (CNRS) UMR 5297, Bordeaux, 33076, France. daniel.choquet@u-bordeaux.fr.
17
Bordeaux Imaging Center, CNRS UMS 3420, University of Bordeaux, INSERM US04, 33076, Bordeaux, France. daniel.choquet@u-bordeaux.fr.

Abstract

Impaired hippocampal synaptic plasticity contributes to cognitive impairment in Huntington's disease (HD). However, the molecular basis of such synaptic plasticity defects is not fully understood. Combining live-cell nanoparticle tracking and super-resolution imaging, we show that AMPAR surface diffusion, a key player in synaptic plasticity, is disturbed in various rodent models of HD. We demonstrate that defects in the brain-derived neurotrophic factor (BDNF)-tyrosine receptor kinase B (TrkB) signaling pathway contribute to the deregulated AMPAR trafficking by reducing the interaction between transmembrane AMPA receptor regulatory proteins (TARPs) and the PDZ-domain scaffold protein PSD95. The disturbed AMPAR surface diffusion is rescued by the antidepressant drug tianeptine via the BDNF signaling pathway. Tianeptine also restores the impaired LTP and hippocampus-dependent memory in different HD mouse models. These findings unravel a mechanism underlying hippocampal synaptic and memory dysfunction in HD, and highlight AMPAR surface diffusion as a promising therapeutic target.

PMID:
30323233
PMCID:
PMC6189172
DOI:
10.1038/s41467-018-06675-3
[Indexed for MEDLINE]
Free PMC Article

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