Regulation of AMPA receptor surface trafficking and synaptic plasticity by a cognitive enhancer and antidepressant molecule
Mol Psychiatry. 2012-06-26; 18(4): 471-484
DOI: 10.1038/mp.2012.80
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The plasticity of excitatory synapses is an essential brain process involved in
cognitive functions, and dysfunctions of such adaptations have been linked to
psychiatric disorders such as depression. Although the intracellular cascades
that are altered in models of depression and stress-related disorders have been
under considerable scrutiny, the molecular interplay between antidepressants and
glutamatergic signaling remains elusive. Using a combination of
electrophysiological and single nanoparticle tracking approaches, we here report
that the cognitive enhancer and 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 plasticity in hippocampal
neurons both under basal conditions and after acute stress. Strikingly,
tianeptine rapidly reduces the surface diffusion of AMPA receptor (AMPAR) through
a Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)-dependent mechanism that
enhances the binding of AMPAR auxiliary subunit stargazin with PSD-95. This
prevents corticosterone-induced AMPAR surface dispersal and restores long-term
potentiation of acutely stressed mice. Collectively, these data provide the first
evidence that a therapeutically used drug targets the surface diffusion of AMPAR
through a CaMKII-stargazin-PSD-95 pathway, to promote long-term synaptic
plasticity.