Dysregulation of olfactory receptor neuron lineage in schizophrenia

Background: Growing evidence implicates abnormal neurodevelopment in schizo phrenia. While neuron birth and differentiation is largely completed by the end of gestation, the olfactory epithelium (OE) is a unique part of the ce ntral nervous system that undergoes regeneration throughout life, thus offe ring an opportunity to investigate cellular and molecular events of neuroge nesis and development postmortem. We hypothesized that OE neurons exhibit d eviant progress through neurodevelopment in schizophrenia characterized by an increase in immature neurons. Methods: Olfactory epithelium was removed at autopsy from 13 prospectively assessed elderly subjects who had schizophrenia and 10 nonpsychiatric contr ol subjects. Sections were immunolabeled with antibodies that distinguish O E neurons in different stages of development, including basal cells (low-af finity nerve growth factor receptor, p75NGFR), postmitotic immature neurons (growth-associated protein 43 [GAP43]), and mature olfactory receptor neur ons (olfactory marker protein). Absolute and relative densities of each cel l type were determined. Results: We observed a significantly lower density of p75NGFR basal cells ( 37%) in schizophrenia and increases in GAP43 + postmitotic immature neurons (316%) and ratios of GAP43 + postmitotic immature neurons to p75NGFR + cel ls (665%) and olfactory marker protein + mature neurons to p75NGFR + basal cells (328%). Neuroleptic-free schizophrenia subjects exhibited the highest GAP43 + postmitotic immature neuron values. Conclusions: Abnormal densities and ratios of OE neurons at different stage s of development indicate dysregulation of OE neuronal lineage in schizophr enia. This could be because of intrinsic factors controlling differentiatio n or an inability to gain trophic support from axonal targets in the olfact ory bulb. While caution is necessary in extrapolating developmental finding s in mature OE to early brain development, similarities in molecular events suggest that such studies may be instructive.