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The synapse, as the site of functional neural interaction, has been suggested as a possible substrate for age-related impairment of cognitive ability. Using the physical disector probe with tissue prepared for ultrastructural analysis, we find an age-related decline in the numerical density of presumptive inhibitory synapses in layer 2 of the sensorimotor cortex of the Brown Norway × Fisher 344 rat. This age-related decline in presumptive inhibitory synapses is maintained when the density of synapses is combined with the numerical density of neurons quantified from the same anatomical space to arrive at a ratio of synapses per neuron. The numerical density of these synapses declines between middle-aged (18 months) and old (29 months) animals by 36% whereas numerical density of neurons does not change between these ages, resulting in a decline in the ratio of presumptive inhibitory synapses per neuron in this cortical area. This study demonstrates a deficit in the intrinsic inhibitory circuitry of the aging neocortex, which suggests an anatomical substrate for age-related cognitive impairment. J. Comp. Neurol. 439:65–72, 2001. © 2001 Wiley-Liss, Inc.