ROLE OF CORTICAL N-METHYL-D-ASPARTATE RECEPTORS IN AUDITORY SENSORY MEMORY AND MISMATCH NEGATIVITY GENERATION - IMPLICATIONS FOR SCHIZOPHRENIA

Working memory refers to the ability of the brain to store and manipul ate information over brief time periods, ranging from seconds to minut es. As opposed to long-term memory, which is critically dependent upon hippocampal processing, critical substrates for working memory are di stributed in a modality-specific fashion throughout cortex. N-methyl-D -aspartate (NMDA) receptors play a crucial role in the initiation of l ong-term memory. Neurochemical mechanisms underlying the transient mem ory storage required for working memory, however, remain obscure. Audi tory sensory memory, which refers to the ability of the brain to retai n transient representations of the physical features (e.g., pitch) of simple auditory stimuli for periods of up to approximately 30 sec, rep resents one of the simplest components of the brain working memory sys tem. Functioning of the auditory sensory memory system is indexed by t he generation of a well-defined event-related potential, termed mismat ch negativity (MMN). MMN can thus be used as an objective index of aud itory sensory memory functioning and a probe for investigating underly ing neurochemical mechanisms. Monkeys generate cortical activity in re sponse to deviant stimuli that closely resembles human MMN. This study uses a combination of intracortical recording and pharmacological mic romanipulations in awake monkeys to demonstrate that both competitive and noncompetitive NMDA antagonists block the generation of MMN withou t affecting prior obligatory activity in primary auditory cortex. Thes e findings suggest that, on a neurophysiological level, MMN represents selective current flow through open, unblocked NMDA channels. Further more, they suggest a crucial role of cortical NMDA receptors in the as sessment of stimulus familiarity/unfamiliarity, which is a key process underlying working memory performance.