The gene BRAF is underexpressed in bipolar subject olfactory neuroepithelial progenitor cells undergoing apoptosis

Background: Bipolar disorder is a devastating psychiatric condition that frequently results in various degrees of brain tissue loss, cognitive decline, and premature death. The documentation of brain tissue loss implicates apoptosis as the likely underlying degenerative process, but direct experimental demonstration is lacking.

Methods: Olfactory neuroepithelial biopsies from individuals with and without bipolar I disorder yielded olfactory neuroepithelial progenitor cells (ONPs), which spontaneously differentiate into neurons and glia. Glutamate, 0.1M, for 3 and 6h was used to induce apoptosis. Genes involved in the apoptotic pathway were interrogated with micro-array analysis before and after glutamate treatment for 6h. Confirmation was accomplished with real-time PCR. Total and phospho-B-Raf protein levels were measured using Western blot analysis.

Results: ONPs from bipolar individuals demonstrated significantly greater apoptosis than cells from non-bipolar subjects. Microarray results revealed 12 differentially expressed genes. Five genes were further examined. BRAF mRNA and protein levels were significantly reduced in bipolar ONPs.

Conclusions: ONPs with the genetic heritage of bipolar I disorder were more sensitive to glutamate induced apoptosis. Under expression of the BRAF gene and protein, which plays a role in regulating the pro-survival MEK/ERK signaling pathway, may contribute to this apoptotic sensitivity.