The applicant's long-term career goal is to develop into an independent investigator studying the etiology of schizophrenia. In order to achieve this objective, the applicant (Dr. Brady Maher) has prepared a Mentored Research Scientist Development Award (KOI) designed to: 1) acquire important technical and theoretical training in molecular biology and in utero electroporation techniques, while investigating gene expression and molecular interactions of schizophrenia susceptibility genes;and 2) prepare a competitive R01 grant proposal in order to establish an independent research program. The training proposed in the KOI application will be conducted in the context of a Career Development Plan. This Career Plan incorporates mentoring from an established molecular neuroscientist (Dr. Joe LoTurco),as well as important training opportunities for practical career development skills, workshops and Responsible Conduct of Research. The applicant as the commitment of resources and expertise from the Univ. of Connecticut, Dept. of Physiology and Neurobiology. The research portion of the Career Plan examines the role of DISCI, a schizophrenia susceptibility gene, in the development of cortical circuits. Dr. Maher's immediate goals are to develop an expertise in molecular biology and in utero electroporation. These techniques will be used to express various molecular constructs of DISCI into the developing mammalian brain to identify molecular signaling cascades important for cortical circuit development. Changes in circuit development will be measured functionally with electrophysiology. The proposed aims will test the hypothesis that mutations in DISCI lead to abnormal circuit formation that underlies schizophrenia. The results from these experiments are expected to increase our understanding of the impact that DISCI has on cortical development. This proposal is highly relevant to public health because approx. 1% of the population suffers from schizophrenia. Results from this proposal will identify important molecular cascades responsible for the etiology of schizophrenia and in so doing will provide potential therapeutic targets for its treatment. The overall training proposed will provide a basis upon which to develop a R01 proposal in Year 3.
The training and research proposed in this grant application are designed to explain how mutations in DISC1, a candidate susceptibility gene, affect the development of the prefrontal cortex. The results obtained from this proposal will provide potential therapeutic targets for the treatment and prevention of schizophrenia and other related disorders.
|Saito, A; Taniguchi, Y; Rannals, M D et al. (2016) Early postnatal GABAA receptor modulation reverses deficits in neuronal maturation in a conditional neurodevelopmental mouse model of DISC1. Mol Psychiatry 21:1449-59|
|Rannals, Matthew D; Hamersky, Gregory R; Page, Stephanie Cerceo et al. (2016) Psychiatric Risk Gene Transcription Factor 4 Regulates Intrinsic Excitability of Prefrontal Neurons via Repression of SCN10a and KCNQ1. Neuron 90:43-55|
|Maher, Brady J; LoTurco, Joseph J (2012) Disrupted-in-schizophrenia (DISC1) functions presynaptically at glutamatergic synapses. PLoS One 7:e34053|
|Zhu, Xiaoqin; Zuo, Hao; Maher, Brady J et al. (2012) Olig2-dependent developmental fate switch of NG2 cells. Development 139:2299-307|
|Girgenti, Matthew J; LoTurco, Joseph J; Maher, Brady J (2012) ZNF804a regulates expression of the schizophrenia-associated genes PRSS16, COMT, PDE4B, and DRD2. PLoS One 7:e32404|