Altered cell cycle dynamics in schizophrenia.

BACKGROUND

The olfactory mucosa, the organ of smell in the nose, is a neural tissue that regenerates new sensory neurons throughout adult life. Based on this tissue, we previously demonstrated increased mitosis in olfactory biopsy cultures from schizophrenia patients compared with healthy control subjects. In addition, neural stem/progenitor cell cultures (neurosphere-derived cells) from nasal biopsies from individuals with schizophrenia show significantly altered gene and protein expression in key cell cycle control pathways.

METHODS

The aim of this study was to investigate cell cycle dynamics in olfactory neurosphere-derived cells from nine male schizophrenia patients and nine male healthy control subjects. Cell cycles were arrested by serum deprivation after which cell population doubling time, proliferation fraction, and cell cycle period were calculated from cell counts over 96 hours. Cell cycle phase was investigated using flow cytometry. Cell lysates were analyzed for expression of cyclin proteins.

RESULTS

Cell population proliferation rate was increased in schizophrenia through a larger pool of proliferating progenitors and a reduced cell cycle period. All phases of the cell cycle were phase-shifted by 2 hours in the schizophrenia-derived cells, which expressed higher levels of the cyclins D1, E, and A2.

CONCLUSIONS

Our observations indicate that schizophrenia is associated with subtle alterations in cell cycle dynamics, shortening of the cell cycle period, and increased expression of G1/S phase cyclins. We speculate that this underlying diathesis could alter the temporal and spatial cascade of brain development and contribute to an altered neurodevelopmental trajectory in schizophrenia.