Bipolar disorder (BP) is among the most important public health problems in the world and is one of the top ten leading causes of lifelong disability Recent large-scale collaborative sample collections along with rapid advances in genome technology are poised to provide statistical evidence of association and/or linkage, but mechanistic understanding of the disease remains at an initial stage. One major limitation that has blocked the progress, although mental disorders such as BP and schizophrenia affect the brain, is the difficulty in accessing neuronal cells from patients. To overcome this dilemma, we have optimized a protocol to enrich olfactory immature neurons from nasal biopsied samples from humans. We previously utilized this methodology to study molecular and cellular profiles of patients with schizophrenia (SZ) and normal controls. Here in this proposal, we plan to use the olfactory epithelium immature neurons (OE neurons) from subjects with psychotic BP, which is familiarly associated with SZ and shares many endophenotypic abnormalities, such as greater severity of cognitive deficits and impaired pre-pulse inhibition. Thus, we hypothesize that such shared abnormalities may stem from molecular and cellular deficits associated with neurodevelopment. To address this hypothesis, we will newly recruit 30 subjects with psychotic and non-psychotic BP, and enrich OE neurons (Aim 1). By using these cells, we will determine development-associated deficits, with an emphasis on Wnt pathway and developmental switch of phospho-DISC1, in psychotic BP. The data will be compared with those from OE neurons from patients with schizophrenia, non-psychotic BP, and normal controls (Aim 2). Then, we will identify gene expression profiles related to Wnt signaling/cilia formation pathways in OE neurons from patients with psychotic BP, in comparison with those from patients with schizophrenia, non-psychotic BP, and controls (Aim 3). This study has the potential to provide important insight into the molecular and cellular signature of psychotic BP associated with neurodevelopment. We expect that some of the major changes may be shared with those in schizophrenia, which contribute to the further study of common susceptibility mechanisms for these disorders.
Based on promising preliminary data, we perform gene expression and functional studies in olfactory neurons from bipolar disorder to address its molecular mechanisms.
|Soda, T; Frank, C; Ishizuka, K et al. (2013) DISC1-ATF4 transcriptional repression complex: dual regulation of the cAMP-PDE4 cascade by DISC1. Mol Psychiatry 18:898-908|