Multidimensional Analysis of Synaptic Dysfunction in Schizophrenia

University Of California-Irvine, Irvine CA

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Abstract

Project Summary Alterations of synaptic function in individuals with schizophrenia have been found in transcriptomics, proteomics, and genome wide association studies. Impaired synaptic glutamatergic (excitatory) and GABAergic (inhibitory) neurotransmission in affected brain regions (e.g. dorsolateral prefrontal cortex; DLPFC) is thought to be involved in the core symptoms of schizophrenia. However, there are no quantitative measurements of synaptic function in the human DLPFC, therefore concrete and specific functional alterations of ion fluxes of glutamate and GABA receptors are lacking. We have begun to address this problem by directly measuring AMPA- and GABA receptor-mediated synaptic currents in postmortem brains from subjects with schizophrenia and contrasting to controls. We demonstrate in our preliminary work that the function of synaptic receptors is maintained in postmortem brains and is significantly decreased in schizophrenia compared to controls. Our overarching hypothesis is that reductions in both inhibitory and excitatory currents underlie synaptic deficits in schizophrenia. We will test rigor and reproducibility of this hypothesis in two larger independent case-control cohorts. These deficits in synaptic currents can be statistically modeled with proteomic and transcriptomic data which will be useful in downstream studies that pharmacologically challenge activation of these currents. In our model, we suggest that an unequal loss of GABAergic and glutamatergic transmission potentially biases circuits towards producing increased inhibition by dual complementary mechanisms. Our novel molecular evidence will be tested in three complementary aims. Aim 1 will test whether there are electrophysiological alterations of the excitatory (E) to inhibitory (I) balance (E/I ratio) in the DLPFC of subjects with schizophrenia compared to controls, by using microtransplantation of synaptic membranes, a novel method that allows for electrophysiological studies of synaptic receptors from postmortem human brain. Aim 2 will test the hypothesis that integration of proteomic, transcriptomic, and electrophysiological data in the same subjects predicts synaptic dysfunction and E/I ratio alterations at the molecular level in SZ. We will use mRNA-Seq in conjunction with label free liquid chromatography-MS (LC-MS/MS) to characterize major synaptic elements with modulatory capacity on GABA and glutamate receptors. Aim 3 will test rigor and reproducibility of electrophysiological data across different brain banks, by using an independent cohort from the NIHM Human Brain Collection Core. Understanding the relationships between parallel transcriptomic and proteomic data sets with the actual dysfunction of synaptic receptors would greatly facilitate targeted pharmacological interventions that help persons suffering with schizophrenia. This approach could benefit other neuropsychiatric disorders involving mood, behavior, and cognition by targeting potential alterations in synaptic function.