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Deconstructing N-Methyl-D-Aspartate Glutamate Receptor Contributions to Cortical Circuit Functions to Construct Better Hypotheses About the Pathophysiology of Schizophrenia

  • John H. Krystal
    Correspondence
    Address correspondence to John H. Krystal, M.D., Department of Psychiatry, Yale University School of Medicine, Suite #901, 300 George Street, New Haven, CT 06511
    Affiliations
    Departments of Psychiatry and Neurobiology, Yale University School of Medicine

    Department of Psychiatry, Yale-New Haven Hospital, New Haven

    Clinical Neuroscience Division, Department of Veterans Affairs National Center for PTSD, VA Connecticut Healthcare, West Haven, Connecticut.
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      One of the challenges facing translational neuroscience is to achieve a deep understanding of how brain circuits represent behavior and the clinical features of psychiatric disorders. Despite progress in understanding working memory, decision making, fear, and some other behaviors, a new generation of advances is needed before we can claim a deep mechanistic understanding of any symptom of any psychiatric disorder. One reason this task is so daunting is that specific molecular abnormalities are recapitulated at multiple sites within individual neurons, microcircuits, and macrocircuits widely distributed in the brain.
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      Linked Article

      • Pyramidal Cell Selective Ablation of N-Methyl-D-Aspartate Receptor 1 Causes Increase in Cellular and Network Excitability
        Biological PsychiatryVol. 77Issue 6
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          Neuronal activity at gamma frequency is impaired in schizophrenia (SZ) and is considered critical for cognitive performance. Such impairments are thought to be due to reduced N-methyl-D-aspartate receptor (NMDAR)-mediated inhibition from parvalbumin interneurons, rather than a direct role of impaired NMDAR signaling on pyramidal neurons. However, recent studies suggest a direct role of pyramidal neurons in regulating gamma oscillations. In particular, a computational model has been proposed in which phasic currents from pyramidal cells could drive synchronized feedback inhibition from interneurons.
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