567. NMDA-mediated neurophysiologic deficits in schizophrenia

Abstract

Deficits in auditory event-related potential (aERP) generation are among the most consistent and robust indices of impaired cortical information processing in schizophrenia. Deficits in P300 generation were first demonstrated over 30 years ago. More recently, deficits have been demonstrated as well in earlier aERP components, including mismatch negativity (MMN) and N1. Both MMN and N1 are obtained under passive attention conditions. Nevertheless, deficits in MMN and N1 generation are as robust as those observed in attentionally demanding paradigms, and reflect impaired ERP generation at the level of auditory sensory cortex. MMN is elicited to deviant stimuli in an auditory oddball paradigm and reflects integrity of auditory sensory (echoic) memory system. N1, in contrast, is observed even to repetitive standard stimuli and reflects stimulus registration within auditory cortex. N1 normally increases with increasing interstimulus interval. In schizophrenia, N1 generation is significantly reduced in amplitude at long, but not short, ISI, reflecting a failure of normal augmentation. Monkeys generate MMN- and N1-like ERP components and can thus be used to evaluate mechanisms underlying cortical information processing. In monkeys, phencyclidine (PCP) and other N-methyl-D-aspartate (NMDA) antagonists induce aERP deficits closely resembling those of schizophrenia. Deficits are associated with decreased NMDA-dependent current flow within supragranular layers of auditory cortex, whereas input to auditory cortex remains intact. These findings indicate that NMDA receptors play a crucial role in cortical response amplification and that deficits in NDMA receptor-mediated neurotransmission may contribute significantly to cortical information processing deficits in schizophrenia.