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
  • 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.

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