MOLECULAR AND GENETIC CORRELATES OF THE ONSET OF SCHIZOPHRENIA

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Schizophrenia (SCZ) is a devastating disease that disturbs the highest order of human brain functions. Many of its symptoms and deficits appear to be mediated by a large-scale prefrontal-limbic neural network (PLN), of which the dorsolateral prefrontal cortex (DLPFC), the anterior cingulate cortex (ACC), the hippocampus (HIPP), and the entorhinal cortex (EC) are key components. This neural system achieves functional maturation during late adolescence and early adulthood, which coincides with the typical age of onset of SCZ. Thus, the neurodevelopmental processes that mediate the maturation of the PLN may directly trigger or indirectly contribute to the onset of illness. At present, our understanding of the periadolescent development of the PLN is very limited. Thus, we will use high magnetic field structural, diffusion tensor, and magnetization transfer neuroimaging to systematically survey the course of periadolescent development of the gray matter and axonal connectivities within the monkey PLN, which is structurally and physiologically similar to its human counterpart. We will then utilize gene expression profiling combined with laser capture microdissection to uncover the genetic correlates of the periadolescent morphological changes of the DLPFC and the HIPP. We postulate that the pattern of gene expression will differ between the 2 regions, reflecing the synaptic reorganization process that is actively taking place during periadolescence in the former but not the latter region. Furthermore, it is hypothesized that the gene expression pattern will be similar between the white matter of the DLPFC and that of the EC, reflecting the concurrent myelination of axons that link subregions of the PLN. Finally, we will compare the periadolescent gene expression profiles of the monkey DLPFC with our existing human prefrontal microarray data obtained from SCZ and normal control subjects in order to identify genes that are differentially expressed both during periadolescent development and in SCZ. Quantitative real-time reverse transcriptase polymerase chain reaction will then be used to confirm these findings. Thus, this proposal seeks to characterize the morphometric maturation of the primate PLN, to define its genetic correlates, and, finally, to identify genes and molecular pathways that may be associated with the onset of SCZ. Ultimately, these data may inspire the conceptualization of novel intervention strategies that may be effective in attenuating or perhaps even preventing the onset of SCZ.