Regulation of AMPA receptor surface trafficking and synaptic plasticity by a cognitive enhancer and antidepressant molecule.
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.
Interdisciplinary Institute for Neuroscience, University of Bordeaux, UMR 5297, Bordeaux, France.
H
H
Zhang
L-A
LA
Etherington
A-S
AS
Hafner
D
D
Belelli
F
F
Coussen
P
P
Delagrange
F
F
Chaouloff
M
M
Spedding
J J
JJ
Lambert
D
D
Choquet
L
L
Groc
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D003345:Corticosterone / Q000494:pharmacology; D000076122:Disks Large Homolog 4 Protein; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects* / Q000502:physiology; D018091:Receptors, AMPA / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism; D013841:Thiazepines / Q000494:pharmacology*; D000096926:Benzenesulfonamides
D000893:Anti-Inflammatory Agents; D000929:Antidepressive Agents, Tricyclic; D001596:Benzylamines; D015220:Calcium Channels; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003345:Corticosterone; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D018091:Receptors, AMPA; D013449:Sulfonamides; D013841:Thiazepines; C113940:Cacng2 protein, mouse; C501447:Dlg4 protein, mouse; C050504:tianeptine; C072105:KN 93; D000096926:Benzenesulfonamides