Expression of WNT Signaling Genes in the Dorsolateral Prefrontal Cortex in Schizophrenia

Gene expression alterations in postmortem schizophrenia tissue are well-documented and are influenced by genetic, medication, and epigenetic factors. The Wingless/Integrated (WNT) signaling pathway, critical for cell growth and development, is involved in various cellular processes including neurodevelopment and synaptic plasticity. Despite its importance, WNT signaling remains understudied in schizophrenia, a disorder characterized by metabolic and bioenergetic defects in cortical regions. In this study, we examined the gene expression of 10 key WNT signaling pathway transcripts: IQGAP1, CTNNβ1, GSK3β, FOXO1, LRP6, MGEA5, TCF4, βTRC, PPP1Cβ, and DVL2 in the dorsolateral prefrontal cortex (DLPFC) using postmortem tissue from schizophrenia subjects (n = 20, 10 males, 10 females) compared to age, pH, and postmortem interval (PMI)-matched controls (n = 20, 10 males, 10 females). Employing the R-shiny application Kaleidoscope, we conducted in silico “lookup” studies from published transcriptomic datasets to examine cell- and region-level expression of these WNT genes. In addition, we investigated the impact of antipsychotics on the mRNA expression of the WNT genes of interest in rodent brain transcriptomic datasets. Our findings revealed no significant changes in region-level WNT transcript expression; however, analyses of previously published cell-level datasets indicated alterations in WNT transcript expression and antipsychotic-specific modulation of certain genes. These results suggest that WNT signaling transcripts may be variably expressed at the cellular level and influenced by antipsychotic treatment, providing novel insights into the role of WNT signaling in the pathophysiology of schizophrenia

P197.02 - Assessment of the Active Kinome in Hippocampal Subfields

This study will use a functional proteomic approach to examine the active kinome in the hippocampus. The active kinome is the global activity of all protein kinases in a system. The hippocampus is subject to dynamic change based on regulatory needs within the system and can therefore contribute to neuroplasticity at a cellular level. The hippocampus has distinct subfields (DG, CA1, CA2, CA3, CA4) and plays a major role in learning and memory. The hippocampal subfields are discrete and have distinct anatomy. Thus, we hypothesize that each subfield has a unique active kinome profile. Differential protein kinase regulation may be essential for molecular plastic changes within the brain. This plasticity is vital for cognitive ability. By identifying the protein kinase activity in each hippocampal subfield, comparisons can be made between subkinomes to better understand signaling pathways associated with memory and learning within the brain. The subfields will be isolated via laser capture microdissection (LCM) and run on the PamGene kinome array. Analysis of the array data will be performed using bioinformatic pipelines. Bioinformatic analyses will identify the kinase activity profiles enriched in different hippocampal subfields . The pipelines used in kinomic analysis are Upstream Kinase Analysis (UKA) and Kinome Random Sampling Analyzer (KRSA). Additionally, pathways will be visualized using Bayesian Network Modeling (KINNET). Hippocampal subfield specific pathways will also be generated. The key kinases investigated and the pathways they belong to will then be compared and contrasted between subfields to paint a clearer picture of how they communicate with one another. These studies will extend our knowledge of signalling mechanisms in the hippocampus and provide a roadmap for interrogating the hippocampus in discrete subfields