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Divergent Effects of Augmenting NMDA Receptor Signaling on Plasticity and Working Memory in Healthy Adults versus Schizophrenia Patients: Importance of Mechanisms Underlying Distinct Cognitive Functions


The N-methyl-D-aspartate glutamate receptor (NMDAR) is a critical substrate underlying experience-dependent plasticity and working memory. NMDAR signaling is impaired in schizophrenia and NMDAR hypofunction may contribute to deficits in plasticity and working memory in schizophrenia. Augmenting NMDAR signaling using the partial agonist d-cycloserine (DCS) may ameliorate such deficits. However, given that divergent properties of the NMDAR underlie its roles in plasticity versus working memory and that various aspects of NMDAR function are abnormal in schizophrenia, examining the effects of DCS in both healthy and patient populations is crucial.

In two study samples, we therefore investigated 100 mg DCS versus placebo on working memory, using a spatial n-back task, and plasticity, using an EEG paradigm that utilizes high frequency visual stimulation (HFvS) to induce long-term potentiation (LTP) in visual cortex neurons and two LTP-dependent learning tasks, the weather prediction and information integration tasks.

In study one among healthy participants, participants who received DCS (n = 32) showed enhanced plasticity compared to placebo (n = 33), as demonstrated by enhanced LTP following HFvS and accelerated acquisition of both learning tasks. Conversely, there were no group differences in working memory. In study two among patients with schizophrenia, patients who received DCS (n = 24) showed enhanced neural responsivity and working memory compared to placebo (n = 21), with no differences on the EEG or learning measures of plasticity.

In healthy participants, DCS therefore enhanced plasticity without affecting working memory, consistent with evidence that beyond a threshold of NMDAR activation needed to generate recurrent firing in working memory circuits, further NMDAR activation should have limited benefits. Conversely, the mirror effects of DCS on baseline neural responsivity and working memory in schizophrenia with no effects on plasticity suggest that DCS ameliorated reductions in NMDAR signaling in schizophrenia, but that increased NMDAR activation was not translated into the structural synaptic changes that support experience-dependent plasticity. Results are consistent with emerging evidence that NMDAR abnormalities in schizophrenia involve not only the receptor but also NMDAR-associated proteins critical for plasticity and highlight the importance of considering how distinct NMDAR properties contribute to individual cognitive deficits in schizophrenia.

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