Aging inverts the effects of p75NTR-modulated mTOR manipulation on hippocampal neuron synaptic plasticity in male mice

Age-induced impairments in learning and memory are in part caused by changes to hippocampal synaptic plasticity during aging. The p75 neurotrophin receptor (p75(NTR)) and mechanistic target of rapamycin (mTOR) are implicated in synaptic plasticity processes. mTOR is also well known for its involvement in aging. Recently, p75(NTR) and mTOR were shown to be mechanistically linked, and that p75(NTR) mediates age-induced impairment of hippocampal synaptic plasticity. Yet the consequences of p75(NTR)-mTOR interaction on hippocampal synaptic plasticity, and the role of mTOR in age-induced cognitive decline, are unclear. In this study, we utilize field electrophysiology to study the effects of mTOR inhibition and activation on long-term potentiation (LTP) in male young and aged wild-type (WT) mice. We then repeated the experiments on p75(NTR) knockout mice. The results demonstrate that mTOR inhibition blocks late-LTP in young WT mice but rescues age-related late-LTP impairment in aged WT mice. mTOR activation suppresses late-LTP in aged WT mice while lacking observable effects on young WT mice. These effects were not observed in p75(NTR) knockout mice. These results demonstrate that the role of mTOR in hippocampal synaptic plasticity is distinct between young and aged mice. Such effects could be explained by differing sensitivity of young and aged hippocampal neurons to changes in protein synthesis or autophagic activity levels. Additionally, elevated mTOR in the aged hippocampus could cause excessive mTOR signaling, which is worsened by activation and alleviated by inhibition. Further research on mTOR and p75(NTR) may prove useful for advancing understanding and, ultimately, mitigation of age-induced cognitive decline.

Automated summary

Age-induced impairments in learning and memory are caused by changes in hippocampal synaptic plasticity. The p75 neurotrophin receptor (p75(NTR)) and mechanistic target of rapamycin (mTOR) are involved in synaptic plasticity processes. The interaction between p75(NTR) and mTOR mediates age-induced impairment of hippocampal synaptic plasticity. However, the specific effects of this interaction and the role of mTOR in age-induced cognitive decline are still unclear.