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The Journal of Neuroscience, January 19, 2005, 25(3):648-651; doi:10.1523/JNEUROSCI.3895-04.2005

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BRIEF COMMUNICATION
How Stress and Fluoxetine Modulate Serotonin 2C Receptor Pre-mRNA Editing

Michael T. Englander,^1,3 Stephanie C. Dulawa,² Punita Bhansali,³ and Claudia Schmauss^1,3

¹Department of Psychiatry and ²Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, New York, 10032, and ³Department of Neuroscience, New York State Psychiatric Institute, New York, New York 10032

In two inbred strains of mice, C57BL/6 and 129Sv, the majority of forebrain neocortical pre-mRNA encoding the serotonin 2C (5-HT_2C) receptor is altered by adenosine-to-inosine editing. As a result, >60% of all mRNAs encode receptors with reduced constitutive and agonist-stimulated activity. However, in the BALB/c strain, a genetically distinct inbred strain with lower forebrain serotonin levels, spontaneously elevated anxiety, and increased stress reactivity, the majority of 5-HT_2C mRNA is nonedited and encodes receptors with the highest constitutive activity and the highest agonist affinity and potency. Neither acute stress (the forced swim test) nor chronic treatment with the serotonin-selective reuptake inhibitor fluoxetine elicit significant changes in 5-HT_2C pre-mRNA editing in C57BL/6 mice. In contrast, exposure of BALB/c mice to acute stress and chronic treatment of nonstressed BALB/c mice with fluoxetine elicit significant, site-specific increases in 5-HT_2C pre-mRNA editing that increase the pool of mRNA encoding receptors with reduced function. These changes in 5-HT_2C pre-mRNA editing resemble those detected previously in the prefrontal cortex of subjects with major depression. However, when chronic fluoxetine treatment is combined with stress exposure of BALB/c mice, these changes in 5-HT_2C pre-mRNA editing are no longer detected. These findings illustrate that 5-HT_2C pre-mRNA editing responses to stress and chronic fluoxetine are modulated by the genetic background, as well as the behavioral state of the animal. They suggest further that the changes in 5-HT_2C pre-mRNA editing found in major depression reflect a previously unrecognized molecular response to stress that can be prevented by chronic antidepressant treatment.

Key words: serotonin 2C receptor; RNA editing; forebrain; inbred mouse strains; stress; antidepressants

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Received Sep 20, 2004; revised November 23, 2004; accepted November 29, 2004.

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