Fellowship-Emily Prantzalos:Role of Neuregulin 3-ErbB4 Signaling in a Murine Model of Co-Morbid Nicotine Dependence and Schizophrenia

Abstract The World Health Organization estimates that 1.3 billion people worldwide are tobacco users and, without cessation support, only 4% of attempts to quit tobacco will succeed. Additionally, the NIH reports a 7.5-fold increase in rates of nicotine dependence among patients with schizophrenia compared to the general population. Both nicotine dependence and schizophrenia have been shown to have strong genetic influences, specifically the gene Neuregulin-3 (NRG3) and its cognate receptor ErbB4. Therefore, the overarching goal of this fellowship-training proposal is to explore the role of the NRG3-ErbB4 signaling pathway in the relationship between nicotine dependence and co-morbid schizophrenia. To accomplish this, we are evaluating two central aims: 1) Determine ErbB4 cell-specific contributions to nicotine withdrawal behavioral phenotypes and efficacy of Aripiprazole in ameliorating these effects, and 2) Characterize expression patterns of NRG3-ErbB4 signaling within the prefrontal cortex and identify the molecular alterations induced during chronic nicotine and withdrawal that may be used as novel drug targets for smoking cessation therapies. Our approach is significant because it utilizes a novel genetic mouse model of both nicotine dependence and schizophrenia in a multidimensional approach to provide insight into the underlying mechanisms that define the NRG3 signaling pathway and its role in nicotine dependence, potentially providing a link between nicotine use and its highly co-morbid psychiatric disorder, schizophrenia.