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

• Published in: Molecular psychiatry Vol. 18; no. 4; pp. 471 - 484
• Main Authors: Zhang, H, Etherington, L-A, Hafner, A-S, Belelli, D, Coussen, F, Delagrange, P, Chaouloff, F, Spedding, M, Lambert, J J, Choquet, D, Groc, L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2013; Nature Publishing Group
• Subjects: 631/378/2591; 631/80/313; 692/699/476; 692/700/565/1436/2185; alpha -Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors; Animals; Anti-Inflammatory Agents - pharmacology; Antidepressants; Antidepressive Agents, Tricyclic - pharmacology; Behavioral Sciences; Benzylamines - pharmacology; Biological and medical sciences; Biological Psychology; Ca super(2+)/calmodulin-dependent protein kinase II; CACNG2 protein; Calcium; Calcium Channels - metabolism; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - antagonists & inhibitors; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Cognitive ability; Cognitive enhancement; Corticosterone - pharmacology; Diffusion; Disks Large Homolog 4 Protein; Dispersal; Drugs; Excitatory Postsynaptic Potentials - drug effects; Guanylate Kinases - metabolism; Health aspects; Hippocampus - drug effects; Hippocampus - metabolism; Intracellular signalling; Kinases; Long-term potentiation; Male; Medical sciences; Medicine; Medicine & Public Health; Membrane Proteins - metabolism; Memory; Mental depression; Mice; Nanoparticles; Neural receptors; Neuronal Plasticity - drug effects; Neuronal Plasticity - physiology; Neuropharmacology; Neuroplasticity; Neurosciences; Original; original-article; Pharmacology. Drug treatments; Pharmacotherapy; Phosphorylation; Physiological aspects; Plasticity (synaptic); Postsynaptic density proteins; Protein Kinase Inhibitors - pharmacology; Protein Transport - drug effects; Protein Transport - physiology; Proteins; Psychiatry; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Receptors, AMPA - metabolism; Salts; Signal transduction; Signal Transduction - drug effects; Sodium; Sulfonamides - pharmacology; Synapses - drug effects; Synapses - metabolism; synaptic depression; Thiazepines - pharmacology; tianeptine; France; United Kingdom; lateral diffusion; stress hormone; glutamate receptor; single nanoparticle tracking; Hormone; Nanoparticle; Psychotropic; Cognition; Glutamate receptor; Stress; Surface; AMPA receptor; Synaptic plasticity; Antidepressant agent
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2012.80

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.