Mounting evidence suggests that schizophrenia is a neurodevelopmental disorder resulting from complex interactions between genetic and environmental factors. In addition to the positive and negative symptoms forming the basis of its diagnosis, schizophrenia is accompanied by abnormal physiological signs or endophenotypes. These are objectively measurable, readily modeled in animals and amenable to genetic linkage analysis. Recently, abnormalities in olfactory function, olfactory bulb (OB) morphology, and olfactory evoked response potentials have been found in people with schizophrenia and their first-degree relatives, indicating that these abnormalities may be endophenotypes of the disorder. Because OB volume reduction could underlie the olfactory function impairment observed in schizophrenia, it is a particularly interesting endophenotype. There is ample evidence that genes modulate variation in OB size and structure. Four quantitative trait loci (QTL), accounting for 20% of the variance in bulb weight, have already been identified in mice. Further identification of correlates between allelic and phenotypic variants at the glomerular, cellular and subcellular levels should be achievable in this highly modular and well-laminated part of the brain and warrants additional study. In doing so, we will move closer to identify the genes involved in OB development and understanding the role of allelic variation in these genes which could be important steps in elucidating the genetic of schizophrenia. In the present study, we propose to:
Aim l: Identify the mechanisms responsible for OB size reduction in schizophrenia. We will use established stereological methods to evaluate the volume of the OB and its layers as well as the number, density and size of its cells in postmortem brain from normal controls and individuals with schizophrenia. These studies will provide detailed morphological information about the OB in schizophrenia and narrow the focus of our mouse QTL study.
Aim 2 : Identify the QTL modulating mouse bulb size at cellular and subcellular levels. This study will explore strain variation in volume, cell number, size and density in OB layers among inbred strains of mice with significantly different bulb size and initiate a complex trait analysis to discover polymorphic genes that modulate OB structure, providing new leads to human studies in schizophrenia. ? ?
