The role of hippocampal GluR1 and GluR2 receptors in manic-like behavior

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

Research output: Contribution to journalArticle

82 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)68-79
Number of pages12
JournalJournal of Neuroscience
Volume28
Issue number1
DOIs
StatePublished - Jan 2 2008

Keywords

  • AMPA
  • Lithium
  • Manic-like behavior
  • PKA
  • Phosphorylation
  • Valproate

ASJC Scopus subject areas

  • Neuroscience(all)

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    Du, J., Creson, T. K., Wu, L. J., Ren, M., Gray, N. A., Falke, C., Wei, Y., Wang, Y., Blumenthal, R., Machado-Vieira, R., Yuan, P., Chen, G., Zhuo, M., & Manji, H. K. (2008). The role of hippocampal GluR1 and GluR2 receptors in manic-like behavior. Journal of Neuroscience, 28(1), 68-79. https://doi.org/10.1523/JNEUROSCI.3080-07.2008