Reduced layer 3 pyramidal cell dendrite length and complexity, spine density, and somal volume have been reported in multiple brain regions, including in primary auditory cortex (AI), in schizophrenia (Sz). Because these structural features are critical for signal processing, they likely underlie the correlated observations of impaired auditory processing and auditory cortex gray matter volume reductions in Sz, and contribute to disability. Dendrite length, complexity, and spine density are shaped by the effects of activity-dependent glutamate signaling on the microtubule and actin cytoskeleton; disruption of this signaling causes structural reductions similar to those in Sz. During the current funding period we have found alterations of proteins at multiple points within this pathway: presynaptic- SYN1, SYP; receptor- GRIA3; signal transduction- kalirin-9, MAP2. These findings have led us to hypothesize that glutamate signaling to the cytoskeleton is altered in AI in Sz, and contributes to the impairments in pyramidal cell structure. We now propose to test this hypothesis in an integrated set of experiments designed to delineate the specific nature of the alterations in these proteins within AI using a combination of targeted proteomics of synaptosomal preparations and quantitative fluorescent microscopy in human tissue (Aim 1 & 2); to determine the mechanisms by which these alterations may lead to morphologic changes in layer 3 pyramidal cells using over-expression and RNAi for WT and mutant kalirin-9, RhoA, RAC1 and MAP2 constructs in vitro and in layer 3 pyramidal cells in AI in vivo (Aim 3); and to place the alterations in the context of the larger glutamate signaling network in AI using targeted proteomics and network co-expression topology analyses (Aim 4).
These Aims provide potential translational impact by examining proteins (i.e. possible drug-able targets) and by the integration of approaches such that alterations can be discovered, and their specificity delineated in diseased tissue, and then their mechanisms determined in model systems. Inclusion of an in vivo model provides a bridge to future studies to test interventions derived from our mechanistic findings with the goal of preventing morphologic changes in layer 3 pyramidal cells in AI and assessing the effects on auditory function.
Individuals with schizophrenia have impairments in auditory cortex structure and function which contribute to disability. We will examine the proteins that comprise the glutamate signaling pathway to determine if they are altered in auditory cortex in schizophrenia and cause the changes in structure we have observed. These studies may lead to treatments that maintain auditory cortex structure and improve its function in disease.
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