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The Journal of Neuroscience, January 2, 2008, 28(1):68-79; doi:10.1523/JNEUROSCI.3080-07.2008

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Behavioral/Systems/Cognitive
The Role of Hippocampal GluR1 and GluR2 Receptors in Manic-Like Behavior

Jing Du,¹ Thomas K. Creson,¹ Long-Jun Wu,² Ming Ren,² Neil A. Gray,¹ Cynthia Falke,¹ Yanling Wei,¹ Yun Wang,¹ Rayah Blumenthal,¹ Rodrigo Machado-Vieira,¹ Peixiong Yuan,¹ Guang Chen,¹ Min Zhuo,² and Husseini K. Manji¹

¹Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20878, and ²Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8

Correspondence should be addressed to Dr. Husseini K. Manji, Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, 9000 Rockville Pike, Building 35, 1C912, Bethesda, MD 20892. Email: manji{at}nih.gov

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.

Key words: lithium; valproate; AMPA; PKA; phosphorylation; manic-like behavior

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Received July 6, 2007; revised Oct. 15, 2007; accepted Nov. 2, 2007.

Correspondence should be addressed to Dr. Husseini K. Manji, Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, 9000 Rockville Pike, Building 35, 1C912, Bethesda, MD 20892. Email: manji{at}nih.gov

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