This translational career development proposal will lead to the mentored training of the Principal Investigator (PI) as a physician scientist expert in engineering and analyzing animal models of schizophrenia and related mental disorders. The PI is clinically trained in psychiatry, and will pursue translational neuroscience research at Columbia University, a leading institution with a strong training history, abundant resources, and mentors and consultants who are leaders in the field of genetic and environmental effects on mouse and human behavior. Using genetic and developmental methods to alter expression of Nrg1 in mice, this proposal will undertake behavioral and neuropathological analyses relevant to psychosis. The PI will be mentored by experts in mouse genetic engineering, Nrg1 structure and function, and brain development. She will undertake biostatistical and research methodology coursework and perform and publish the research project with the goal of becoming an independent investigator. Nrg1 has been genetically associated with schizophrenia and endophenotypes of schizophrenia such as sensory motor gating (Pre-pulse inhibition), abnormal social behavior, working memory deficits, and altered brain morphology. MicroRNA technology will be utilized with control both by Tetracycline responsive promoters and by Cre recombinase activation. Animals transgenic for the microRNA will inhibit Nrg1 expression in a reversible time specific manner only when exposed to tetracycline compounds during brain development, and in a cell type specific manner. The investigator will explore abnormal behaviors in adult mice with various times of developmental knockdown of Nrg1 to determine the key period of neurodevelopmental sensitivity and potential reversibility. The neuronal and glial cell types critical for these endophenotypes will be explored in the second stage of these experiments. The exploration of this and future animal models will guide future clinical research on timing of preventative intervention in schizophrenia, and also provides a mechanism for detecting therapeutic targets and testing efficacy. Tracing the developmental courses of the underlying pathogenic and pathophysiologic abnormalities of mental disorders is key to fulfilling the NIMH strategic aims. By more closely modeling the underlying pathology, mutant animal systems have the potential to accelerate the discovery of new preventative and therapeutic agents, as well as model gene by environment interactions.
Schizophrenia is a severely disabling illness that begins to affect young adults at the peak of their social development. Genetics and neuroscience now allow the modeling of abnormal brain development in animals. Development of animals with mutant Neuregulin 1 molecules will provide critical information about the timing and targets of treatments for prevention and allow testing of new therapeutic agents for efficacy.
|Karam, Caline S; Ballon, Jacob S; Bivens, Nancy M et al. (2010) Signaling pathways in schizophrenia: emerging targets and therapeutic strategies. Trends Pharmacol Sci 31:381-90|