Linking Redox Regulation of NMDAR Synaptic Function to Cognitive Decline during Aging

NMDA receptors (NMDARs) play a critical role in learning and memory; however, there is a lack of evidence for a direct relationship between a well characterized decline in NMDAR function and impaired cognition during aging. The present study was designed to test the idea that a redox-mediated decrease in the NMDAR component of synaptic transmission during aging is related to a specific cognitive phenotype: impaired memory for rapidly acquired novel spatial information. Young and middle-aged male F344 rats were provided 1d of training on the spatial version of the water maze, and retention was examined 24 h later. The performance of young rats was used as a criterion for classifying middle-aged rats as impaired and unimpaired on the task. Subsequent construction of CA3-CA1 synaptic input-output curves in hippocampal slices confirmed an age-related decrease in synaptic responses, including the NMDAR component of synaptic transmission. Examination of synaptic transmission according to behavioral classification revealed that animals classified as impaired exhibited a decrease in the total and the NMDAR component of the synaptic response relative to unimpaired animals. Furthermore, bath application of the reducing agent dithiothreitol increased the NMDAR component of the synaptic response to a greater extent in impaired animals relative to unimpaired and young rats. These results provide evidence for a link between the redox-mediated decline in NMDAR function and emergence of an age-related cognitive phenotype, impairment in the rapid acquisition and retention of novel spatial information.