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

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

  • Nat Commun. 2018 Oct 15;9(1):4272. doi: 10.1038/s41467-018-06675-3.
Hongyu Zhang 1 2 3,  Chunlei Zhang 4 5,  Jean Vincent 4 5,  Diana Zala 6 7,  Caroline Benstaali 8 9,  Matthieu Sainlos 4 5,  Dolors Grillo-Bosch 4 5,  Sophie Daburon 4 5,  Françoise Coussen 4 5,  Yoon Cho 10,  Denis J David 11,  Frederic Saudou 12 13 14,  Yann Humeau 4 5,  Daniel Choquet 15 16 17
Affiliations

Affiliations

  • 1 Interdisciplinary Institute for Neuroscience, University of Bordeaux, Bordeaux, 33076, France. [email protected].
  • 2 Interdisciplinary Institute for Neuroscience, Centre National de la Recherche Scientifique (CNRS) UMR 5297, Bordeaux, 33076, France. [email protected].
  • 3 Department of Biomedicine, KG Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Jonas Lies vei 91, N-5009, Bergen, Norway. [email protected].
  • 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. [email protected].
  • 13 INSERM, U1216, F-38000, Grenoble, France. [email protected].
  • 14 CHU Grenoble Alpes, F-38000, Grenoble, France. [email protected].
  • 15 Interdisciplinary Institute for Neuroscience, University of Bordeaux, Bordeaux, 33076, France. [email protected].
  • 16 Interdisciplinary Institute for Neuroscience, Centre National de la Recherche Scientifique (CNRS) UMR 5297, Bordeaux, 33076, France. [email protected].
  • 17 Bordeaux Imaging Center, CNRS UMS 3420, University of Bordeaux, INSERM US04, 33076, Bordeaux, France. [email protected].
PMID: 30323233 DOI: 10.1038/s41467-018-06675-3
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.

Figures
Products