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

Hongyu Zhang, Chunlei Zhang, Jean Vincent, Diana Zala, Caroline Benstaali, Matthieu Sainlos, Dolors Grillo-Bosch, Sophie Daburon, Françoise Coussen, Yoon Cho, Denis J. David, Frederic Saudou, Yann Humeau, Daniel Choquet
Nat Commun. 2018-10-15; 9(1):
DOI: 10.1038/s41467-018-06675-3

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1. 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.

Zhang H(1)(2)(3), Zhang C(4)(5), Vincent J(4)(5), Zala D(6)(7), Benstaali
C(8)(9), Sainlos M(4)(5), Grillo-Bosch D(4)(5), Daburon S(4)(5), Coussen F(4)(5),
Cho Y(10), David DJ(11), Saudou F(12)(13)(14), Humeau Y(4)(5), Choquet
D(15)(16)(17).

Author information:
(1)Interdisciplinary Institute for Neuroscience, University of Bordeaux,
Bordeaux, 33076, France. .
(2)Interdisciplinary Institute for Neuroscience, Centre National de la Recherche
Scientifique (CNRS) UMR 5297, Bordeaux, 33076, France. .
(3)Department of Biomedicine, KG Jebsen Centre for Research on Neuropsychiatric
Disorders, University of Bergen, Jonas Lies vei 91, N-5009, Bergen, Norway.
.
(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. .
(13)INSERM, U1216, F-38000, Grenoble, France. .
(14)CHU Grenoble Alpes, F-38000, Grenoble, France. .
(15)Interdisciplinary Institute for Neuroscience, University of Bordeaux,
Bordeaux, 33076, France. .
(16)Interdisciplinary Institute for Neuroscience, Centre National de la Recherche
Scientifique (CNRS) UMR 5297, Bordeaux, 33076, France.
.
(17)Bordeaux Imaging Center, CNRS UMS 3420, University of Bordeaux, INSERM US04,
33076, Bordeaux, France. .

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.

DOI: 10.1038/s41467-018-06675-3
PMCID: PMC6189172
PMID: 30323233


Auteurs Bordeaux Neurocampus