Increased susceptibility to induction of long-term depression and long-term potentiation reversal during aging

Homosynaptic long-term depression (LTD) and reversal of long-term potentiation (LTP) were examined extracellularly at CA3-CA1 synapses in stratum radiatum of slices from adult (6-9 months) and aged (20-24 months) Fischer 344 rats. Prolonged low-frequency stimulation (LFS) (900 pulses/1 Hz) of the Schaffer collaterals depressed the initial slope of the excitatory postsynaptic potential (EPSP) in aged but not adult rats. LTD at aged synapses was pathway-specific, persistent, and sensitive to the NMDA receptor antagonist DL-2-amino-5-phosphonopentanoic acid (AP5). Adult slices exhibited AP5-sensitive LTD in high [Ca2+] medium, whereas LTD in aged slices was blocked by high [Mg2+], suggesting that differences in Ca2+ regulation may underlie susceptibility to LTD. Despite age-related differences in LTD induction, no age difference in LTP magnitude was revealed. Additionally, LFS delivered 60 min after LTP induction resulted in similar LTP reversal for both age groups. Susceptibility differences to LTP reversal were indicated after multiple short-duration LFS bursts (30 pulses/1 Hz), with each burst separated by 10 min. Aged synapses exhibited significant reversal after a single burst and complete reversal after three LFS episodes. In adult slices, LTP reversal appeared after the fourth burst, and at no time was LTP depressed to initial baseline levels. This study provides the first characterization of homosynaptic LTD/LTP reversal in the aged animal and demonstrates that one form of plasticity, depression attributable to LFS, is increased during aging.