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J. Biol. Chem., Vol. 283, Issue 25, 17194-17204, June 20, 2008

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Activation of 5-HT_2A/C Receptors Counteracts 5-HT_1A Regulation of N-Methyl-D-aspartate Receptor Channels in Pyramidal Neurons of Prefrontal Cortex^*

From the Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York, Buffalo, New York 14214

Abnormal serotonin-glutamate interaction in prefrontal cortex (PFC) is implicated in the pathophysiology of many mental disorders, including schizophrenia and depression. However, the mechanisms by which this interaction occurs remain unclear. Our previous study has shown that activation of 5-HT_1A receptors inhibits N-methyl-D-aspartate (NMDA) receptor (NMDAR) currents in PFC pyramidal neurons by disrupting microtubule-based transport of NMDARs. Here we found that activation of 5-HT_2A/C receptors significantly attenuated the effect of 5-HT_1A on NMDAR currents and microtubule depolymerization. The counteractive effect of 5-HT_2A/C on 5-HT_1A regulation of synaptic NMDAR response was also observed in PFC pyramidal neurons from intact animals treated with various 5-HT-related drugs. Moreover, 5-HT_2A/C stimulation triggered the activation of extracellular signal-regulated kinase (ERK) in dendritic processes. Inhibition of the β-arrestin/Src/dynamin signaling blocked 5-HT_2A/C activation of ERK and the counteractive effect of 5-HT_2A/C on 5-HT_1A regulation of NMDAR currents. Immunocytochemical studies showed that 5-HT_2A/C treatment blocked the inhibitory effect of 5-HT_1A on surface NR2B clusters on dendrites, which was prevented by cellular knockdown of β-arrestins. Taken together, our study suggests that serotonin, via 5-HT_1A and 5-HT_2A/C receptor activation, regulates NMDAR functions in PFC neurons in a counteractive manner. 5-HT_2A/C, by activating ERK via the β-arrestin-dependent pathway, opposes the 5-HT_1A disruption of microtubule stability and NMDAR transport. These findings provide a framework for understanding the complex interactions between serotonin and NMDARs in PFC, which could be important for cognitive and emotional control in which both systems are highly involved.

Received for publication, March 3, 2008 , and in revised form, April 25, 2008.

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^* This work was supported, in whole or in part, by National Institutes of Health Grants MH63128 and NS48911. This work was also supported by a National Alliance for Research on Schizophrenia and Depression (NARSAD) Independent Investigator Award (to Z. Y.) and a NARSAD Young Investigator Award (to E. Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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¹ To whom correspondence should be addressed: Dept. of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York, 124 Sherman Hall, Buffalo, NY 14214. Tel.: 716-829-3058; Fax: 716-829-2699; E-mail: zhenyan{at}buffalo.edu.

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