Modulation of AMPA receptor surface diffusion restores hippocampal plasticity and memory in Huntington’s disease models
Year: 2018
Type: article
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.
Source: Nature Communications
Institutions: Centre National de la Recherche Scientifique, Université de Bordeaux, Institut Interdisciplinaire de Neuroscience, University of Bergen, Inserm, Centre for Psychiatry and Neuroscience, Institut Curie, Grenoble Institute of Neurosciences, Université Grenoble Alpes, Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, Université Paris-Sud, Université Paris-Saclay, Centre de recherche en Epidémiologie et Santé des Populations, Santé mentale et santé publique, Bordeaux Imaging Center
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G2450198060, G381665449, G5332433398, Bordeaux Region Aquitaine Initiative for Neuroscience, G7240651115, Synaptic correlates of learning and memory dysfunction analysed by super-resolution STED microscopy in the hippocampus in vivo, Développment d'une infrastructure française distribuée coordonnée, G8694042055, Towards high spatio-temporal control of endogenous AMPA receptors short and long term synaptic plasticity
OpenAlex ID: W2897775066