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Dysregulation of Olfactory Receptor Neuron Lineage in Schizophrenia
Steven E. Arnold, MD;
Li-Ying Han, MS;
Paul J. Moberg, PhD;
Bruce I. Turetsky, MD;
Raquel E. Gur, MD, PhD;
John Q. Trojanowski, MD, PhD;
Chang-Gyu Hahn, MD, PhD
Arch Gen Psychiatry. 2001;58:829-835.
Background Growing evidence implicates abnormal neurodevelopment in schizophrenia.
While neuron birth and differentiation is largely completed by the end of
gestation, the olfactory epithelium (OE) is a unique part of the central nervous
system that undergoes regeneration throughout life, thus offering an opportunity
to investigate cellular and molecular events of neurogenesis and development
postmortem. We hypothesized that OE neurons exhibit deviant 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 control subjects.
Sections were immunolabeled with antibodies that distinguish OE neurons in
different stages of development, including basal cells (low-affinity nerve
growth factor receptor, p75NGFR), postmitotic immature neurons (growth-associated
protein 43 [GAP43]), and mature olfactory receptor neurons (olfactory marker
protein). Absolute and relative densities of each cell 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 + cells (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 stages of development
indicate dysregulation of OE neuronal lineage in schizophrenia. This could
be because of intrinsic factors controlling differentiation or an inability
to gain trophic support from axonal targets in the olfactory bulb. While caution
is necessary in extrapolating developmental findings in mature OE to early
brain development, similarities in molecular events suggest that such studies
may be instructive.
From the Laboratory for Cellular and Molecular Neuropathology, Center
for Neurobiology and Behavior (Drs Arnold and Hahn and Ms Han) and the Schizophrenia
Mental Health Clinical Research Center (Drs Arnold, Moberg, Turetsky, Gur,
and Trojanowski), and the Departments of Psychiatry and Pathology and Laboratory
Medicine (Dr Trojanowski), University of Pennsylvania, Philadelphia.
Corresponding author: Steven E. Arnold, MD, 142 Clinical Research
Bldg, 415 Curie Blvd, Philadelphia, PA 19104 (e-mail: sarnold{at}mail.med.upenn.edu).
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