Title: Independent Effects of Paternal Age and Neuregulin1 Expression in Mice in Relation to Schizophrenia
Description: This thesis work is divided into two parts, both guided by the overwhelming evidence that hereditary factors influence neurodevelopment. The first section is focused on advanced paternal age, which may modulate an offspring's place on the continuum of normal behavior, as well as conferring increased risk for the development of certain disorders, such as schizophrenia. By using a mouse model to examine the difference between old and young father offspring, we have been able to flesh out this phenotype. Additionally, by examining the female and male offspring separately, we discovered gender-specific differences between the groups. Ongoing work is seeking to identify changes in methylation between the old and young father offspring that may explain these differences. The second section deals with a specific gene that has been linked to schizophrenia, namely Neuregulin1. This gene plays several roles in neurodevelopement, notably including the proliferation of interneurons and their incorporation into the cortex and olfactory bulb.

We used heterozygous mice to explore the effects of a change in gene expression of the proliferation of new neurons from the subventricular zone, their migration through the rostral migratory stream, and differentiation into various interneuron subtypes in the olfactory bulb. The heterozygotes appeared to have decreased turnover of a subset of calretinin-expressing interneurons of the granule cell layer. We also treated subgroups of these mice with clozapine, however this did not seem to have any effect. We looked at the olfactory system in this work since this is a model of neurogenesis that continues into adulthood. Yet the regions that produce cortical interneurons during early development give rise to the subventricular zone. Therefore the findings related to subventricular zone neurogenesis may have similar implications for cortical development.