Neurophysiological mechanisms of cortical plasticity impairments in schizophrenia and modulation by the NMDA receptor agonist D-serine

Joshua T. Kantrowitz*, Michael L. Epstein, Odeta Beggel, Stephanie Rohrig, Jonathan M. Lehrfeld, Nadine Revheim, Nayla P. Lehrfeld, Jacob Reep, Emily Parker, Gail Silipo, Merav Ahissar, Daniel C. Javitt

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

70 Scopus citations


Schizophrenia is associated with deficits in cortical plasticity that affect sensory brain regions and lead to impaired cognitive performance. Here we examined underlying neural mechanisms of auditory plasticity deficits using combined behavioural and neurophysiological assessment, along with neuropharmacological manipulation targeted at the N-methyl-D-aspartate type glutamate receptor (NMDAR). Cortical plasticity was assessed in a cohort of 40 schizophrenia/schizoaffective patients relative to 42 healthy control subjects using a fixed reference tone auditory plasticity task. In a second cohort (n = 21 schizophrenia/schizoaffective patients, n = 13 healthy controls), event-related potential and event-related time-frequency measures of auditory dysfunction were assessed during administration of the NMDAR agonist D-serine. Mismatch negativity was used as a functional read-out of auditory-level function. Clinical trials registration numbers were NCT01474395/NCT02156908. Schizophrenia/schizoaffective patients showed significantly reduced auditory plasticity versus healthy controls (P = 0.001) that correlated with measures of cognitive, occupational and social dysfunction. In event-related potential/time-frequency analyses, patients showed highly significant reductions in sensory N1 that reflected underlying impairments in θ responses (P < 0.001), along with reduced θ and β-power modulation during retention and motor-preparation intervals. Repeated administration of D-serine led to intercorrelated improvements in (i) auditory plasticity (P < 0.001); (ii) θ-frequency response (P < 0.05); and (iii) mismatch negativity generation to trained versus untrained tones (P = 0.02). Schizophrenia/schizoaffective patients show highly significant deficits in auditory plasticity that contribute to cognitive, occupational and social dysfunction. D-serine studies suggest first that NMDAR dysfunction may contribute to underlying cortical plasticity deficits and, second, that repeated NMDAR agonist administration may enhance cortical plasticity in schizophrenia.

Original languageAmerican English
Pages (from-to)3281-3295
Number of pages15
Issue number12
StatePublished - Dec 2016

Bibliographical note

Funding Information:
This work was supported in part by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Number UL1 RR024156 and the Dr Joseph E. And Lillian Pisetsky Young Investigator Award for Clinical Research in Serious Mental Illness to J.T.K. and by the NIH grants (P50 MH086385, R01 MH049334) to D.C.J. J.T.K reports having received consulting payments within the last 24 months from Vindico Medical Education, Annenberg Center for Health Sciences at Eisenhower, Health Advances, LLC, Strategic Edge Communications, Transperfect, Slingshot Insights, Kinetix Group, Havas Life and Cowen and Company. He has conducted clinical research supported by the NIMH, the Stanley Foundation, Roche-Genetech, Alkermes, Merck, Lundbeck, Forum, Sunovion, Novartis, Pfizer and Lilly. He owns a small number of shares of common stock in GlaxoSmithKline. D.C.J. reports having received consulting payments within the last 2 years from Sunovion, Forum, and Takeda. He has received research support from Roche. He holds intellectual property rights for use of NMDA modulators in treatment of neuropsychiatric disorders. He holds equity in Glytech, AASI, and NeuroRx, and serves on the advisory board of Promentis and NeuroRx. All other co-authors report no conflicts or disclosures.

Publisher Copyright:
© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.


  • Clinical trials
  • Cortical plasticity
  • Imaging
  • Schizophrenia
  • Social cognition


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