Reduced phosphorylation of GluA1 subunits relates to anxiety-like behaviours in mice.
Anxiety and depression are highly prevalent and frequently co-morbid conditions. The ionotropic glutamate receptors N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) mediate actions of monoaminergic antidepressants and have been directly targeted by novel fast-acting antidepressants. Less is known about the role of these receptors in anxiety-like states. Here we investigate how two distinct anxiolytic agents, buspirone, a partial 5-HT(1A) agonist, and diazepam, a benzodiazepine, influence phosphorylation of GluA1 subunits of AMPA receptors at the potentiating residue Ser(845) and Ser(831) in corticolimbic regions. To test the functional relevance of these changes, phosphomutant GluA1 mice lacking phosphorylatable Ser(845) and Ser(831) were examined in relevant behavioural paradigms. These mutant mice exhibited a reduced anxiety-like phenotype in the light/dark exploration task and elevated plus maze, but not in the novelty induced hypophagia paradigm. These data indicate that reduced potentiation of the AMPA receptor signalling, via decreased GluA1 phoshorylation, is specifically involved in approach-avoidance based paradigms relevant for anxiety-like behaviours.
Laboratory of Translational Neuropharmacology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. carly.kiselycznyk@yale.edu
Carly
C
Kiselycznyk
Xiaoqun
X
Zhang
Richard L
RL
Huganir
Andrew
A
Holmes
Per
P
Svenningsson
D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D005260:Female; D055879:Gene Knock-In Techniques; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010766:Phosphorylation / Q000502:physiology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism
D021122:Protein Subunits; D018091:Receptors, AMPA; D012694:Serine