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Augmenting NMDA Receptor Signaling Boosts Experience-Dependent Neuroplasticity in the Adult Human Brain
Forsyth JK, Bachman P, Mathalon DH, Roach BJ, and Asarnow RF
Proceedings of the National Academy of Sciences, 2015, Published Online

Experience-dependent plasticity is a fundamental property of the brain. It is defined as 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.  Experience-dependent plasticity 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. 

Graduate student Jennifer Forsyth in collaboration with her mentor, Dr. Peter Bachman, and others 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 task 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 weather prediction task and the information integration task. 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.

The results of this study are significant for future lines of research.  Findings by Dr. Bachman and his colleagues provide evidence that enhancing signaling at the glutamate N-methyl-D-aspartate receptor 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.

Contributors:
Jennifer K. Forsyth, MA and Peter Bachman, PhD (Department of Psychiatry, University of Pittsburgh)

Daniel H. Mathalon, PhD, MD (Department of Psychiatry, University of California/San Francisco and San Francisco Veterans Affairs Medical Center)

Brian J. Roach, PhD, MS (San Francisco Veterans Affairs Medical Center)

Robert F. Asarnow, PhD (Departments of Psychology and Psychiatry and Biobehavioral Sciences, University of California, Los Angeles)

This article appears in the Proceedings of the National Academy of Sciences. To view the abstract, click here.