Effects of short-term synaptic plasticity on primary auditory cortex

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Abstract

When humans receive a sequence of repeated auditory stimuli, the appearance of a deviating stimulus will result in a neural cortical response termed mismatch negativity (MMN). Alterations to amplitude and latency of MMN is repeatedly linked to schizophrenia (sz). The mechanism behind MMN is thought to be stimulus-specific adaptation (SSA), created by short-term synaptic plasticity (STP) in the primary auditory cortex (A1). New evidence from genetic and proteomic studies in sz patients indicate a modification to synaptic proteins. In sz mouse models, knockout of the post-synaptic density protein PSD-93 reduces paired-pulse facilitation, an observation that could be linked to altered STP. The multi-scaled data was integrated through computational modeling, using an SSA model to study the effect of altered STP in auditory MMN using genetic data from sz animal models. It was found that reductions in PSD-93 replicated altered SSA in response to an oddball protocol. Filtering of the SSA data generated a signal comparable to EEG measurements of MMN, with model reductions of PSD-93 corresponding to experimental observations of reduced MMN in sz patients. A simulation of ketamine was found to have similar effects on SSA and MMN as decreased PSD-93, supporting the hypothesis of an altered post-synaptic density as the basis for findings of reduced MMN in sz patients. An extension introducing variability of synaptic transmission allowed for a larger model parameter space, resulting in simulation outputs with a closer resemblance to sz experimental results. The model is well on its way to successfully connect findings of PSD-93 with MMN and could be a future basis for finding potential drug targets and developing animal behavioral experiments relating to sz.