NMDA-Receptor Dysfunction Disrupts Serial Biases in Spatial Working Memory

Abstract

In working memory (WM) tasks, attractive biases to previous items are evidence for continuous temporal integration of memories. These serial biases have been modeled as a product of synaptic short-term plasticity, allowing WM representations to endure in a synaptic trace and interfere with the next trial even when neural activity returns to baseline values. We hypothesized that the NMDAR, a key component of both short-term potentiation (STP) and stable WM delay activity, would be of central importance to serial biases in a visuospatial WM task. Confirming this hypothesis, we found drastically reduced biases in patients with anti-NMDAR encephalitis and schizophrenia, both diseases that have been related to NMDAR hypofunction. We simulated serial biases in a spiking neural network supported by a Hebbian STP mechanism that builds up during persistent delay-activity. We found a close correspondence between patient and model behavior when gradually lowering levels of STP, suggesting a disruption of short-term plasticity in associative cortices of schizophrenic and anti-NMDAR encephalitis patients. Further, we explored the capability of the model to explain reduced biases in light of the disinhibition theory of schizophrenia.