Regulation of AMPA receptor surface trafficking and synaptic plasticity by a cognitive enhancer and antidepressant molecule

• DOI: 10.1038/mp.2012.80
• Publication Date: 2012-06-26T12:37:29Z
• Authors: H Zhang; L-A Etherington; A-S Hafner; D Belelli; F Coussen; P Delagrange; F Chaouloff; M Spedding; J J Lambert; D Choquet; L Groc
• Keywords: Tianeptine; Long-term depression

The plasticity of excitatory synapses is an essential brain process involved in cognitive functions, and dysfunctions such adaptations have been linked to psychiatric disorders as depression. Although the intracellular cascades that are altered models depression stress-related under considerable scrutiny, molecular interplay between antidepressants glutamatergic signaling remains elusive. Using a combination electrophysiological single nanoparticle tracking approaches, we here report enhancer antidepressant tianeptine (S 1574, [3-chloro-6-methyl-5,5-dioxo-6,11-dihydro-(c,f)-dibenzo-(1,2-thiazepine)-11-yl) amino]-7 heptanoic acid, sodium salt) favors synaptic hippocampal neurons both basal conditions after acute stress. Strikingly, rapidly reduces surface diffusion AMPA receptor (AMPAR) through Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)-dependent mechanism enhances binding AMPAR auxiliary subunit stargazin with PSD-95. This prevents corticosterone-induced dispersal restores long-term potentiation acutely stressed mice. Collectively, these data provide first evidence therapeutically used drug targets CaMKII-stargazin-PSD-95 pathway, promote plasticity.