Abstract
Working memory is the ability to hold information “online” over a time delay in order to perform a task. This kind of memory is encoded in the brain by persistent neural activity that outlasts the presentation of a stimulus. Patients with schizophrenia perform poorly in working memory tasks that require the brief memory of a target location in space. This deficit indicates that persistent neural activity related to spatial locations may be impaired in the disease. At the circuit level, many studies have shown that NMDA receptors and the dopamine system are involved in both schizophrenia pathology and working memory-related persistent activity. In this Hypothesis and Theory article, we examine the possible connection between NMDA receptors, the dopamine system, and schizophrenia-linked working memory deficits. In particular, we focus on the dopamine breakdown product homocysteine (HCY), which is consistently elevated in schizophrenia patients. Our previous studies have shown that HCY strongly reduces the desensitization of NMDA currents. Here, we show that HCY likely affects NMDA receptors in brain regions that support working memory; this is because these areas favor dopamine breakdown over transport to clear dopamine from synapses. Finally, within the context of two NMDA-based computational models of working memory, we suggest a mechanism by which HCY could give rise to the working memory deficits observed in schizophrenia patients.
Highlights
The purpose of this Hypothesis and Theory article is to lay groundwork for linking two findings that are typically observed in subjects with schizophrenia: spatial working memory deficits and elevated homocysteine (HCY) levels
We present a theory within the context of computational models of persistent neural activity through which HCY may affect neural circuits that mediate spatial working memory
These results suggest that there may be a genetic contribution to working memory failure, which resembles the partial genetic basis of schizophrenia itself (e.g., Torrey et al, 1994)
Summary
The purpose of this Hypothesis and Theory article is to lay groundwork for linking two findings that are typically observed in subjects with schizophrenia: spatial working memory deficits and elevated homocysteine (HCY) levels. We briefly explain these two findings, simultaneously illustrating their possible relationship within a framework of dopaminergic physiology. We present a theory within the context of computational models of persistent neural activity through which HCY may affect neural circuits that mediate spatial working memory. We suggest future experiments based on our theory
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