Abstract
Cognitive deficits in schizophrenia have been hypothesized to be caused by altered
synaptic transmission in circuits of the prefrontal cortex. 2 main hypotheses have
been put forward: reduced inhibition and hypofunctional NMDA receptors. Recently,
Lee et al. (2008) found that spatial working memory deficits in schizophrenic patients
include a disproportionately high incidence of high-confidence error responses. Here,
we have studied what synaptic dysfunction can generate this specific behavioral deficit
using a computational network model of spatial working memory. We developed quantitative
behavioral readout from our network simulations, which reflected the qualitative properties
of underlying neural dynamics. We then analyzed the behavioral effect of the GABAergic
and glutamatergic hypotheses on our network simulations. We found that reduction in
inhibitory transmission in the network caused a reduction in performance through an
increase of high-confidence errors, as in the experimental data. In contrast, a concerted
reduction in NMDA-receptor-dependent transmission reduced performance via increased
low-confidence errors. Only when NMDA receptors were specifically depleted in interneurons
did the behavioral read-out of our network mimic the behavioral results for schizophrenic
patients. Thus, dynamics in our model network support a role of both global inhibition
reduction and hypofunctional NMDA receptors in interneurons in generating the behavioral
deficits of simple spatial working memory tasks in schizophrenia.
Key words
delayed response - prefrontal cortex - NMDA receptor - inhibition - network - attractor
