Modulation of AMPA receptor surface diffusion restores hippocampal plasticity and memory in Huntington's disease models. Issue 1 (December 2018)

• Record Type: Journal Article
• Authors: Zhang, Hongyu; Zhang, Chunlei; Vincent, Jean; Zala, Diana; Benstaali, Caroline; Sainlos, Matthieu; Grillo-Bosch, Dolors; Daburon, Sophie; Coussen, Françoise; Cho, Yoon; David, Denis; Saudou, Frederic; Humeau, Yann; Choquet, Daniel
• Is Part Of: Nature communications. Volume 9:Issue 1(2018)
• Page Start: 1
• Page End: 16
• Publication Date: 2018-12
• Subjects: Biology -- Periodicals; Physical sciences -- Periodicals; 505
• DOI: 10.1038/s41467-018-06675-3
• Languages: English
• ISSNs: 2041-1723

Abstract

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. Cognitive decline in Huntington's disease (HD) may be due to impaired hippocampal synaptic plasticity. In this study the authors show that AMPA receptor surface diffusion, a key player in synaptic plasticity, is deregulated in multiple HD mouse models as a result of impaired BDNF signalling that underlies the memory deficits, and can be pharmacologically rescued.