Augmenting NMDA receptor signaling boosts experience-dependent neuroplasticity in the adult human brain

Abstract

Experience-dependent plasticity is a fundamental property of the brain. It is critical for everyday function, is impaired in a range of neurological and psychiatric disorders, and frequently depends on long-term potentiation (LTP). Preclinical studies suggest that augmenting N-methyl-D-aspartate receptor (NMDAR) signaling may promote experience-dependent plasticity; however, a lack of noninvasive methods has limited our ability to test this idea in humans until recently. We examined the effects of enhancing NMDAR signaling using D-cycloserine (DCS) on a recently developed LTP EEG paradigm that uses high-frequency visual stimulation (HFvS) to induce neural potentiation in visual cortex neurons, as well as on three cognitive tasks: a weather prediction task (WPT), an information integration task (IIT), and a n-back task. The WPT and IIT are learning tasks that require practice with feedback to reach optimal performance. The n-back assesses working memory. Healthy adults were randomized to receive DCS (100 mg; n = 32) or placebo (n = 33); groups were similar in IQ and demographic characteristics. Participants who received DCS showed enhanced potentiation of neural responses following repetitive HFvS, as well as enhanced performance on the WPT and IIT. Groups did not differ on the n-back. Augmenting NMDAR signaling using DCS therefore enhanced activitydependent plasticity in human adults, as demonstrated by lasting enhancement of neural potentiation following repetitive HFvS and accelerated acquisition of two learning tasks. Results highlight the utility of considering cellular mechanisms underlying distinct cognitive functions when investigating potential cognitive enhancers.D-cycloserine | NMDA receptor | neuroplasticity | long-term potentiation | learning E xperience-dependent neuroplasticity is the capacity of the brain to change in response to environmental input, learning, and use. It is a fundamental property of the brain and is critical for everyday functioning. It allows us to learn and remember patterns, predict and obtain reward, and refine and accelerate response selection for adaptive behavior (1). During development, experience-dependent plasticity interacts with genetic programming to organize neurons into the structurally and functionally connected circuits that characterize a mature brain. Although this basic circuitry is established by early adulthood, experience-dependent plasticity continues to shape connectivity within these circuits such that important inputs and action outputs are represented by larger and more coordinated populations of neurons. Given that these changes are the primary means through which the adult brain enables new behavior and that such plasticity is impaired in a range of neurological and psychiatric disorders (2), identifying manipulations that can harness experiencedependent plasticity offers exciting possibilities. Here, we tested whether augmenting N-methyl-D-aspartate receptor (NMDAR) activity could enhance experience-dependent plasticity in the adult human brain.The ...

Effects of Augmenting N-Methyl-D-Aspartate Receptor Signaling on Working Memory and Experience-Dependent Plasticity in Schizophrenia: An Exploratory Study Using Acute d-cycloserine

“…In contrast to our prior findings of DCS in healthy adults, 50 schizophrenia patients who received DCS performed similarly to patients who received placebo across electrophysiological and learning measures of plasticity. Conversely, among patients who performed above chance, patients who received DCS showed superior 2-back working memory performance compared to patients who received placebo.…”

“…29,30 Indeed, we previously found that augmenting NMDAR signaling using DCS in healthy adults enhanced VEP potentiation following HFvS and IIT and WPT learning. 50 Controlling for antipsychotic dose, sex, age, and IQ did not alter the similarity of placebo and DCS schizophrenia patients on the plasticity measures, nor did excluding patients who performed around chance for each learning task. Given that the current patients were relatively high-functioning, had low symptom levels, and that the same subgroup of DCS patients showed superior working memory performance over placebo, it is unlikely that confounding factors such as lack of motivation, inattention, or difficulty understanding the tasks accounts for the lack of group differences on plasticity.…”

“…In healthy adults, we previously found that participant performance on a second day of WPT and IIT testing started at the same level as the end of practice on the first day of testing. 50 Thus, we viewed a between-subject design as the most practical approach given the practice effects observed on these experiencedependent plasticity tasks. However, given this limitation, the modest sample size, and the fact that beneficial effects of DCS on the N-back were only found in the subgroup of patients who were defined behaviorally as adequately engaging in the task, independent replication is essential, including using a within-subject design for nonplasticity measures.…”

“…45,46 Given evidence that repeated DCS dosing may desensitize the NMDAR complex, [47][48][49] we used a single dose of DCS. In our prior study among healthy adults, acute DCS enhanced experience-dependent plasticity, 50 as demonstrated by enhanced visual evoked potentials (VEPs) following high-frequency visual stimulation (HFvS) and enhanced learning on 2 cortico-striatal dependent learning tasks: the weather prediction task (WPT) 51 and information integration task (IIT). 52 In contrast, DCS did not affect performance on a N-back working memory task that was identical to the IIT in stimuli and trial structure.…”

Enhancing NMDA Receptor Function: Recent Progress on Allosteric Modulators

“…In recent years, a few clinical trials have shown efficacy of NMDAR enhancers in schizophrenia, such as DCS, sarcosine, and sodium benzoate. Participants receiving DCS showed enhanced potentiation of neural responses and cognitive performance [64, 65]. Sodium benzoate, as a d-amino acid oxidase inhibitor, significantly improved the PANSS total score and neurocognition in chronic schizophrenia patients [66] (ClinicalTrials.gov NCT00960219.…”