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

Significance Experience-dependent plasticity is the capacity of the brain to undergo changes following environmental input and use, and is a primary means through which the adult brain enables new behavior. In the current study, we provide evidence that enhancing signaling at the glutamate N-methyl-d-aspartate receptor (NMDAR) can enhance the mechanism underlying many forms of experience-dependent plasticity (i.e., long-term potentiation of synaptic currents) and also enhance experience-dependent learning in healthy adult humans. This suggests exciting possibilities for manipulating plasticity in adults and has implications for treating neurological and neuropsychiatric disorders in which experience-dependent plasticity is impaired. 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 activity-dependent 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.

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