OLFACTORY NEURODEVELOPMENTAL PATHOLOGY IN SCHIZOPHRENIA

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Growing evidence from clinical and postmortem research implicates abnormal neurodevelopment in the pathophysiology of schizophrenia. While neuron birth, migration, differentiation, and connectivity are largely completed by the end of gestation in almost all parts of the CNS, the olfactory epithelium and olfactory bulb are unique in that they undergo continuous regeneration and reinnervation throughout life. Thus, they offer an opportunity to investigate cellular and molecular events of ongoing neuronal and connectional development, even in late life. In addition, cytoarchitectural abnormalities suggestive of abnormal development have been described in olfactory cortices, although findings remain controversial. The importance of examining the olfactory system in schizophrenia is further underscored by the marked impairments in odor detection, identification, and memory that are present in the disorder. The proposed research will characterize neurodevelopmental processes in human olfactory epithelium, olfactory bulb, and primary olfactory cortices in well-characterized individuals with schizophrenia and matched controls. Our overarching hypothesis is that abnormal patterns of molecular, cellular and connectional neurodevelopment are evident in olfactory regions in schizophrenia. In the olfactory epithelium (Aim 1), immunohistochemistry with cell-type-specific antibodies and computer-assisted microscopy will be used to determine the relative proportions and morphologic characteristics of differentiating cell types in the olfactory receptor neuron lineage, as well as their expression of polypeptides that are important for the neuronal cytoskeleton and for neurotrophin mediated signal transduction. In the olfactory bulb (Aim 2), the cellular, dendritic, and axonal composition of the glomerulus will be quantified after immunolabeling for synaptophysin, tyrosine hydroxylase, calretinin, calbindin D28k, NCAMs and GAP- 43. In Aim 3, we will perform a quantitative cytoarchitectural analysis of piriform and entorhinal cortices. The relative densities of immunohistochemically distinct populations of neurons will be determined and the spatial arrangement of neurons will be assessed using spatial point pattern analyses.