Modulation of synaptic plasticity by antimanic agents: the role of AMPA glutamate receptor subunit 1 synaptic expression.
Increasing data suggest that impairments of cellular plasticity underlie the pathophysiology of bipolar disorder. In this context, it is noteworthy that AMPA glutamate receptor trafficking regulates synaptic plasticity, effects mediated by signaling cascades, which are targets for antimanic agents. The present studies were undertaken to determine whether two clinically effective, but structurally highly dissimilar, antimanic agents lithium and valproate regulate synaptic expression of AMPA receptor subunit glutamate receptor 1 (GluR1). Chronic (but not acute) treatment of rats with therapeutically relevant concentrations of lithium or valproate reduced hippocampal synaptosomal GluR1 levels. The reduction in synaptic GluR1 by lithium and valproate was attributable to a reduction of surface GluR1 distribution onto the neuronal membrane as demonstrated by three independent assays in cultured hippocampal neurons. Furthermore, these agents induced a decrease in GluR1 phosphorylation at a specific PKA site (GluR1p845), which is known to be critical for AMPA receptor insertion. Sp-cAMP treatment reversed the attenuation of phosphorylation by lithium and valproate and also brought GluR1 back to the surface, suggesting that phosphorylation of GluR1p845 is involved in the mechanism of GluR1 surface attenuation. In addition, GluR1p845 phosphorylation also was attenuated in hippocampus from lithium- or valproate-treated animals in vivo. In contrast, imipramine, an antidepressant that can trigger manic episodes, increased synaptic expression of GluR1 in hippocampus in vivo. These studies suggest that regulation of glutamatergically mediated synaptic plasticity may play a role in the treatment of bipolar disorder and raise the possibility that agents more directly affecting synaptic GluR1 may represent novel therapies for this devastating illness.
Du
Jing
J
Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, Bethesda, Maryland 20892, USA.
Gray
Neil A
NA
Falke
Cynthia A
CA
Chen
Wenxin
W
Yuan
Peixiong
P
Szabo
Steven T
ST
Einat
Haim
H
Manji
Husseini K
HK
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D018692:Antimanic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015870:Gene Expression; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology; D016651:Lithium Carbonate / Q000494:pharmacology*; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000032:analysis / Q000378:metabolism* / Q000502:physiology; D013569:Synapses / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D014635:Valproic Acid / Q000494:pharmacology*
D000929:Antidepressive Agents, Tricyclic; D018692:Antimanic Agents; D017868:Cyclic AMP-Dependent Protein Kinases; D007099:Imipramine; D016651:Lithium Carbonate; D018091:Receptors, AMPA; D014635:Valproic Acid; C104723:glutamate receptor ionotropic, AMPA 3; C104722:glutamate receptor ionotropic, AMPA 2