Dysregulation of olfactory receptor neuron lineage in schizophrenia.
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.
Arnold
S E
SE
Center for Neurobiology and Behavior, University of Pennsylvania, 142 Clinical Research Bldg, 415 Curie Blvd, Philadelphia, PA 19104, USA. sarnold@mail.med.upenn.edu
Han
L Y
LY
Moberg
P J
PJ
Turetsky
B I
BI
Gur
R E
RE
Trojanowski
J Q
JQ
Hahn
C G
CG
D000368:Aged; D014150:Antipsychotic Agents / Q000627:therapeutic use; D002452:Cell Count; D002455:Cell Division / Q000502:physiology; D005260:Female; D019922:GAP-43 Protein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009416:Nerve Regeneration / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D051842:Olfactory Marker Protein; D009831:Olfactory Mucosa / Q000166:cytology / Q000378:metabolism; D018034:Olfactory Receptor Neurons / Q000166:cytology* / Q000378:metabolism; D011446:Prospective Studies; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D012559:Schizophrenia / Q000175:diagnosis* / Q000378:metabolism; D012907:Smoking / Q000378:metabolism
D014150:Antipsychotic Agents; D019922:GAP-43 Protein; D009419:Nerve Tissue Proteins; C497597:OMP protein, human; D051842:Olfactory Marker Protein; D017475:Receptors, Nerve Growth Factor