This is a revised R01 application to investigate abnormalities of signaling networks in pyramidal neurons in schizophrenia. It is an understatement to say that the treatment of schizo-spectrum disorders has not progressed in the past 25 years, since the development of atypical antipsychotics. However, there is broad consensus that these newer medications do not extend the efficacy of pharmacological treatments to cognitive and negative/deficit symptoms, which lead to profound disability in a large number of persons afflicted with schizophrenia. While effective for the psychotic, or positive symptoms, all antipsychotic medications are associated with significant side effects, and have high rates of discontinuation. We posit that abnormalities of cortical pyramidal neurons underlie many of the cognitive deficits observed in the schizophrenia phenotype, including abnormalities of working memory, executive function, and motivation. Pyramidal neurons typically project to other cortical regions (superficial pyramidal cells, in layers II and III) or subcortically (deep pyramidal cells, in layers V and VI) to the thalamus, striatum, and other basal ganglia. Divergent abnormalities of superficial and deep pyramidal neurons in schizophrenia may arise from neurodevelopmental insults that reflect differences in the circuitry of these cell types, resulting in altered gene expression profiles, neuronal migration, and/or aberrant connectivity of these neurons. We hypothesize that abnormalities of pyramidal neurons extend well beyond simple measures of gene expression, and include disease- and lamina- specific changes in functionally related signaling networks. To address this problem, we adapted a novel ?omics? bioinformatics approach for analysis of serine/threonine sub-kinomes in postmortem brain tissue, and identified high-yield protein kinase targets for further study. We propose to focus in this application on two of our high- yield ?hits? from these hypothesis generating preliminary studies: AKT and PKA. Specifically, we will test the hypothesis that these kinases are differentially regulated in superficial and deep pyramidal neurons in schizophrenia. We will use an innovative approach that combines standard techniques, including laser capture microdissection and biochemical kinase activity assays, to measure pyramidal neuron-specific kinase expression and activity in schizophrenia. We will follow up on these studies by measuring expression of factors downstream from AKT and PKA, including phosphoproteins and related networks of mRNAs. Finally, we propose two discrete in silico studies, one focused on developing pyramidal neuron-specific signaling models in schizophrenia, and the other focused on integration of our data with cutting-edge bioinformatics databases, to identify pathways associated with standardized pathophysiological disease-drug dyads. These innovative studies will identify pyramidal neuron-specific signaling pathways disrupted in schizophrenia and provide new ideas regarding the pathophysiology and the development of novel treatment strategies for this often devastating illness.
This project will identify the critical elements of brain function that contribute to the pathophysiology of schizophrenia. Identification of the molecular elements underlying schizophrenia will provide new targets for the development of medicines to treat this illness.
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| Funk, Adam J; Mielnik, Catharine A; Koene, Rachael et al. (2017) Postsynaptic Density-95 Isoform Abnormalities in Schizophrenia. Schizophr Bull 43:891-899 |
