Daniel Javitt - NMDAR dysfunction in schizophrenia Implications for pathophysiology and basic neuro

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Schizophrenia (Sz) is a major mental disorder that affects ~1% of the population. Although traditional models of Sz focused on dopaminergic dysfunction, newer models increasingly implicate glutamatergic systems, particularly N-methyl-D-aspartate receptors (NMDAR). NMDAR models are supported by the ability of NMDAR antagonists (e.g. PCP, ketamine) to induce symptoms and neurocognitive deficits closely resembling those of Sz and by genetic and auto-immune findings. One key deficit related to NMDAR dysfunction in Sz is a failure in the generation of mismatch negativity (MMN). Deficit in MMN generation have been extensively replicated in Sz and shown to predict functional outcome. At the physiological level, MMN impairments are related to impaired theta (4-7 Hz) generation within somatomotor networks. At the cognitive level, deficits in basic auditory processing contribute to impairments in phonological reading and auditory emotion recognition which, in turn, contribute to poor psychosocial function.In the visual system, NMDAR play a preferential role in non-linear gain which, in turn, particularly affects functioning of the magnocellular visual system. Thus, consistent impairments are observed in ERP (e.g. visual P1) and fMRI response to magnocellular-biased visual static and motion stimuli, while responses to parvocellular-biased stimuli remain relatively intact. Deficits in magnocellular function in turn lead to impairments in higher order visual information processing, including ability to detect and process facial expression. As with auditory deficits, basic visual deficits contribute directly to social dysfunction and impaired functional outcome. Overall patterns of dysfunction in Sz highlight the role played by NMDAR in information processing at the ensemble and network levels.