Background: Schizophrenia is a complex genetic disorder affecting at least 1% of the population. While its etiopathogenesis is unknown, evidence accrues for a formulation of it being a disorder of the synapse, glutamatergic transmission, myelin dysregulation, and of connectivity. Evidence for dysregulation of synaptic genes in schizophrenia (SZ) suggests that SZ-relevant neuropathology involves dysfunction of the cellular machinery in neurons. The thalamus is comprised of discrete neuronal subpopulations reciprocally connected to previously-implicated SZ-associated cortical areas (i.e.: anterior nucleus [AN] to cingulate cortex, a cortical region recently identified as a cortical region most vulnerable in SZ). Volume and neuronal loss in thalamic subregions and dysfunctional glucose uptake in the thalamus and its reciprocal cortical circuitry suggest that thalamic dysfunction plays an important role in SZ. Methods: In postmortem samples (n=15, each) from SZ and non-psychiatric subjects we will isolate neurons from AN and posterior ventral medial nucleus [VMpo], extract total RNA, isolate and T-7 linearly amplify mRNAs for whole genome screening using Affymetrix U133 Plus 2.0 GeneChips. We will select transcripts according to stringent statistical methods (i.e.: fold change criteria >1.7, FDR <5%, signal intensity) and use both manually curated pathway analysis tools (i.e.: Ingenuity), along with KEGG, BIOCARTA and GeneOntology to identify significantly dysregulated genes and functional pathways in SZ for qRT-PCR validation.
Specific aims : 1. To find RNA-specific transcriptome alterations in neurons from the anterior (principal) nucleus [AN] (previously implicated in SZ) and posterior portion of ventral medial nucleus [VMpo] (non-SZ associated) of the thalamus in order to identify the underlying molecular mechanisms, pathways, protein-protein or molecule- protein interactions involved in SZ. 2. To identify region-specific gene expression patterns from thalamic neuronal subpopulations in SZ. The relevance of this project to the public health is to identify the gene expression profiles from cells in brain sub regions in the thalamus that have previously been identified as affected in persons suffering with schizophrenia. This effort may give new information regarding disease processes involved in schizophrenia which may help either in new approaches to diagnosis or medication development. ? ?
