The role of hippocampal GluR1 and GluR2 receptors in manic-like behavior.
The cellular basis underlying the complex clinical symptomatology of bipolar disorder and the mechanisms underlying the actions of its effective treatments have not yet been fully elucidated. This study investigated the role of hippocampal synaptic AMPA receptors. We found that chronic administration of the antimanic agents lithium and valproate (VPA) reduced synaptic AMPA receptor GluR1/2 in hippocampal neurons in vitro and in vivo. Electrophysiological studies confirmed that the AMPA/NMDA ratio was reduced in CA1 regions of hippocampal slices from lithium-treated animals. Reduction in GluR1 phosphorylation at its cAMP-dependent protein kinase A site by the synthetic peptide TAT-S845, which mimics the effects of lithium or VPA, was sufficient to attenuate surface and synaptic GluR1/2 levels in hippocampal neurons in vitro and in vivo. Intrahippocampal infusion studies with the AMPA-specific inhibitor GYKI 52466 [4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-5-yl)-benzenamine hydrochloride], a GluR1-specific TAT-S845 peptide, showed that GluR1/2 was essential for the development of manic/hedonic-like behaviors such as amphetamine-induced hyperactivity. These studies provide novel insights into the role of hippocampal GluR1/2 receptors in mediating facets of the manic syndrome and offer avenues for the development of novel therapeutics for these disorders.
Du
Jing
J
Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20878, USA.
Creson
Thomas K
TK
Wu
Long-Jun
LJ
Ren
Ming
M
Gray
Neil A
NA
Falke
Cynthia
C
Wei
Yanling
Y
Wang
Yun
Y
Blumenthal
Rayah
R
Machado-Vieira
Rodrigo
R
Yuan
Peixiong
P
Chen
Guang
G
Zhuo
Min
M
Manji
Husseini K
HK
D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology; D001714:Bipolar Disorder / Q000188:drug therapy / Q000473:pathology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D011921:Rats, Inbred WKY; D018091:Receptors, AMPA / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D014635:Valproic Acid / Q000494:pharmacology
D018692:Antimanic Agents; D001569:Benzodiazepines; D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D014635:Valproic Acid; C061950:GYKI 52466; C104722:glutamate receptor ionotropic, AMPA 2