Modulation of Neuronal Excitability by Serotonin-NMDA Interactions in Prefrontal Cortex

Abstract

Both serotonin and NMDA signaling in prefrontal cortex (PFC) are implicated in mental disorders, including depression and anxiety. To understand their potential contributions to PFC neuronal excitability, we examined the effect of co-activation of 5-HT and NMDA receptors on action potential firing elicited by depolarizing current injection in PFC pyramidal neurons. In the presence of NMDA, a low concentration of the 5-HT 1A agonist 8-OH-DPAT substantially reduced the number of spikes, and a low concentration of the 5-HT 2A/C agonist α-Me-5HT significantly enhanced it, while both agonists were ineffective when applied alone. The 8-OH-DPAT effect on firing was mediated by inhibition of protein kinase A (PKA), whereas the α-Me-5HT effect was mediated by activation of protein kinase C (PKC). Moreover, the extracellular signal-regulated kinase (ERK), a signaling molecule downstream of PKA and PKC, was involved in both 5-HT 1A and 5-HT 2A/C modulation of neuronal excitability. Biochemical evidence showed that 5-HT 1A decreased, whereas 5-HT 2A/C increased the activation of ERK in an NMDA-dependent manner. In animals exposed to acutely stress, the enhancing effect of 5-HT 2A/C on firing was lost, while the decreasing effect of 5-HT 1A on firing was intact. Concomitantly, the effect of 5-HT 2A/C , but not 5-HT 1A , on ERK activation was abolished in stressed animals. Taken together, our results demonstrate that distinct 5-HT receptor subtypes, by interacting with NMDA receptors, differentially regulate PFC neuronal firing, and the complex effects of 5-HT receptors on excitability are selectively altered under stressful conditions, which are often associated with mental disorders.Keywords 5-HT 1A receptor; 5-HT 2 receptor; NMDA receptor; action potential firing; ERK; stress; prefrontal cortexThe prefrontal cortex (PFC) receives a dense serotonergic innervation from the raphe nuclei (Smiley and Goldman-Rakic, 1996). The serotonergic system plays an important role in regulating PFC functions, including emotional control, cognitive behaviors and working memory (Williams et al., 1996;Buhot 1997;Williams et al., 2002). Aberrant serotonin system * Correspondence should be addressed to ZhenYan, Ph.D., Department of Physiology and Biophysics, State University of New York at Buffalo, 124 Sherman Hall, Buffalo, NY, 14214, USA. Email: zhenyan@buffalo.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. This PDF receipt will only be used as the basis for generating PubMed Central (PMC) documents. PMC documents will be made available for review after conversion (approx. 2-3 weeks time)...

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