Mouse models of human psychiatric disorders show that chronic stress can lead to depression. Mice lacking 5HT2CR show signs of stress response, hyperactivity, increased appetite and obesity. 5HT2CR mRNA is edited by two enzymes ADAR1 and ADAR2 that belong to a family of enzymes known as adenonsine deaminases that act on RNA (ADAR). ADAR1 and ADAR2 catalyze the conversion of adenosine to inosine in mRNA and therefore have the ability to change amino acid codons that can produce numerous isoforms of proteins. ADAR2 is able to autoedit its own transcript resulting in a truncated protein. To test whether autoediting is a regulatory mechanism, ADAR2 transgenic mice were generated that over express ADAR2 cDNA. The result was the development of a mouse with unique set of phenotypic alterations. First the transgenic mice became extremely obese that was mature onset. Paired feeding studies showed ADAR2 transgenic mice exhibit increased food intake without any apparent metabolic dysregulation. Prior to obesity the ADAR2 transgenic mice have normal plasma glucose, insulin and leptin levels but they have elevated levels of corticosterone. Most provocative is that when compared with age and weight-matched control littermates, ADAR2 transgenic mice have increased immobility time in both the Porsolt swim and tail suspension test. The Porsolt swim and tail suspension tests are reproducible and predictable for screening antidepressants. This may suggest that ADAR2 transgenic mice are a model of depression related behaviors. Several lines of evidence have implicated 5HT2CR in psychiatric disorders including depression. A gain or loss of 5HT2CR as a result of RNA editing is a potential mechanism for generating psychopathology. One of the consequences of ADAR2 RNA editing is alterations in the 5HT2CR. The hypothesis to be tested in the present application is that ADAR2 transgenic mice have altered 5HT2CR editing in brain subregions that have been implicated in depression, and hence have a blunted serotonin synaptic function which induces depression-like behavioral changes. Further characterization of depression-related behaviors and regional RNA editing of 5HT2CR in the brain of ADAR2 transgenic mice and their response to specific antidepressant drugs will provide an opportunity to evaluate a potentially valuable animal model of psychological depression and to gain insight into the mechanisms of this form of affective disorder.

Public Health Relevance

The applicant has recently developed a new line of transgenic mouse that may have direct clinical relevance for the treatment of psychological depression. This application focuses on validation of the ADAR2 transgenic mouse as a model of psychological depression and the role of serotonin 2C receptor RNA editing leading to depression. The model may also be useful in examining neuronal substrates or loci involved in depression. Predicting clinical outcomes from a rodent model of psychological depression may further prove to be useful for understanding the efficacy and tolerability of antidepressants.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-BDCN-A (90))
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Beckel-Mitchener, Andrea C
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University of Iowa
Schools of Arts and Sciences
Iowa City
United States
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Akubuiro, A; Bridget Zimmerman, M; Boles Ponto, L L et al. (2013) Hyperactive hypothalamus, motivated and non-distractible chronic overeating in ADAR2 transgenic mice. Genes Brain Behav 12:311-22
Singh, M; Singh, M M; Na, E et al. (2011) Altered ADAR 2 equilibrium and 5HT(2C) R editing in the prefrontal cortex of ADAR 2 transgenic mice. Genes Brain Behav 10:637-47