Age-related differences in resting glutamate levels and glutamate uptake in the hippocampus and frontal cortex of C57BL/6 mice.

In normal aging, little is known in human and animal models about functional changes to glutamate neuronal systems that may contribute to age-related cognitive differences. The present studies investigated glutamate neuronal signaling in the hippocampus (dentate gyrus) and frontal cortex (infralimbic) of young adult (3-8 months), middle-aged (10-13 months), and aged (15-27 months) male and female C57BL/6 mice using microelectrode electrode array (MEA) recording technology to measure second-by-second resting levels of glutamate in anesthetized mice. Glutamate regulation was investigated in vivo by inhibiting the uptake of glutamate by local application of the competitive non-transportable blocker of excitatory amino acid transporters DL-threo-beta-benzyloxyaspartate (TBOA). Resting levels of glutamate and TBOA-induced changes in extracellular glutamate concentration were reliably measured in the hippocampus and frontal cortex of young adult, middle-aged, and aged mice and were seen to significantly increase in aging in the hippocampus. In the frontal cortex we observed an increase only in the middle-aged animals. TBOA produced robust changes in extracellular glutamate in the hippocampus and frontal cortex which showed significant changes in the kinetics of the signals in the middle-aged mice. Interestingly, the variance of the resting glutamate levels in the hippocampus of aged female mice was greater than in aged male mice, supporting a possible age-related gender difference in glutamate function. Taken together, these data support that glutamate signaling in the hippocampus and frontal cortex of aged mice is affected in normal aging with changes in glial regulation of glutamate uptake observed from the TBOA effects in the middle-aged mice.