Schizophrenia is a chronic psychiatric disorder with several cognitive and negative symptoms, including deficits in attention and memory, social withdrawal, and difficulty processing information. As well as being linked to long-term prognosis and self-care, these symptoms are the most resistant to treatment. Recently, there has been growing interest in the olfactory deficits seen in schizophrenia, which are strongly linked to development of negative and cognitive symptoms. A genetic mutation in Nrg1 is sufficient to reproduce these olfactory deficits in mice. This project will use a novel genetic knockdown approach and indelible lineage fate mapping techniques to study the function of Nrg1 in proliferation and migration of neuroblasts from the subventricular zone (SVZ), and survival and differentiation of these cells as they travel to the olfactory bulb (OB). To allow indelible marking of cells, the estrogen responsive Nestin-CreERT2 mouse line has been bred to a reporter line expressing floxed enhanced yellow fluorescent protein (EYFP). This results in 50% staining of a timed cohort of immature neural progenitor cells when mice are treated briefly with tamoxifen. It is then possible to trace these marked cells through migration and differentiation. We have also designed a mutant mouse expressing the NTG transgene, an inhibitory microRNA that silences Nrg1 and requires the transactivator rtTA for expression and Doxicycline (Dox). The NTG line is maintained on an rtTA*M2 strain that displays universal expression of rtTA. This will result in a global knockdown of Nrg1 when these mice are given Doxycycline. Breeding these transgenic mice with the Nestin-CreERT2/EYFP mice will result in mice that display an inducible global knockdown of Nrg1 and exhibit fluorescent labeling of a timed cohort of SVZ progenitor cells, when given chronic Doxycycline and pulse treated with Tamoxifen. This system will be used to determine the effects of Nrg1 knockdown on the proliferation, survival, migration, and differentiation of SVZ progenitor cells as they travel through the rostral migratory stream (RMS) to the olfactory bulb. This project will form the basis of research training for an MD/PhD candidate from an underrepresented minority group and also support clinical training with the long-term goal of developing the candidate into a physician scientist and principal investigator in medical research, focusing on the neurosciences.
Schizophrenia is a chronic disorder that affects 1% of the world's population and places an enormous mental and emotional burden on its victims and those around them. Neuregulin-1 (Nrg1) has been genetically associated with schizophrenia, and our model of Nrg1 knockdowns will allow us to define its role in development and clarify the gene's role in schizophrenia vulnerability. Knowledge of the mechanism of susceptibility will allow for the development of more targeted and effective treatments.
