AbstractThe 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.