PROJECT SUMMARY/ABSTRACT: Schizophrenia (Sz) patients show reduced neuroplasticity during training on exercises that place implicit, increasing demands on early auditory information processing. As improved auditory processing can facilitate gains in those cognitive processes that are more proximal to daily functioning (verbal memory, executive functioning), enhancing neuroplasticity for better auditory processing represents an unmet clinical need and a rate-limiting first step prior to remediating cognition and overall function. Over recent years, N-methyl-D-aspartate-type glutamate receptor (NMDAR) glycine site agonists such as D- serine have increasingly been shown to facilitate neuroplasticity in both Sz and healthy volunteers, particularly when combined with cognitive remediation. NMDAR agonists appear to be maximally effective for neuroplasticity when used repeatedly at non-daily intervals in a dose dependent manner, the optimal dose (80, 100 or 120 mg/kg) remains an open question, as does the ability of combined D-serine + neuroplasticity-based auditory learning to produce sustained, functional improvement. D-serine leads to highly significant, acute improvement in both auditory neuroplasticity and the NMDAR sensitive early auditory processing measure mismatch negativity (MMN) when given prior to two 1x weekly sessions of a brief, neuroplasticity-based auditory remediation program. Plasticity improvements correlated with reading and working memory suggesting plasticity improvements are predictive of functionally of relevant outcomes. The ultimate goal of this is to enhance efficacy and efficiency of cognitive remediation by augmenting with D- serine. First, during the R61, I will confirm target engagement, relationships of plasticity changes and functional outcomes and the optimal dose of D-serine treatment. Successful completion of the R61 is defined by ≥moderate acute effect size change in auditory plasticity, MMN and a moderate effect size correlation with functionally relevant cognitive measures. During the three-year R33, I will conduct a randomized, placebo- controlled, parallel group study of D-serine, assessing the sustained effects of D-serine + 16 sessions (1x week) of neuroplasticity-based auditory remediation. Most successful, cognitive remediation programs are limited by lengthy (30-50 hrs) treatment regimens. Hypothesizing that adding D-serine will increase efficiency of cognitive remediation, successful completion of the R33 is defined as significant improvement in global cognition after 16 hours of treatment. Results will be relevant not only to auditory plasticity in Sz, but also to use of NMDAR drugs to augment remediation across neurocognitive disorders and domains, use of ERP to monitor effects and benefits of an abbreviated cognitive remediation program, and will serve as a pilot study to determine whether future, definitive clinical trials are warranted.