Transcriptomic profiling and electrophysiological analysis from microtransplanted synaptic membranes

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 voltage gated ion channels 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 independent case-control cohorts. These deficits in synaptic currents can be statistically modeled with transcriptomic data which will be useful in downstream studies that pharmacologically challenge activation of these currents. (1)Test the hypothesis that alterations of the excitatory to inhibitory balance are present in schizophrenia (SZ) brains using microtransplantation of synaptic membranes (MSM) in the DLPFC of schizophrenia cases (n = 15) and controls (n = 15). We measured ion currents of microtransplanted neurotransmitter receptors into frog oocytes using two electrode voltage clamp. (2) Test the hypothesis that integrative analysis of transcriptomic data predicts synaptic dysfunction in SZ at the electrophysiological level. The physiological and pharmacological profile of synaptic AMPA and GABA receptors are mostly determined by their subunit composition, posttranslational modifications, and associated proteins. We collected RNA-seq to characterize genes in the synapse that predict electrophysiological responses.