It has been shown that presenilin is involved in maintaining Ca²⁺ homeostasis in neurons, including regulating endoplasmic reticulum (ER) Ca²⁺ storage. From studies of primary cultures and cell lines, however, its role in stress-induced responses is still controversial. In the present study we analyzed the effects of presenilin mutations on membrane currents and synaptic functions in response to stress using an in vivo preparation. We examined voltage-gated K⁺ and Ca²⁺ currents at the Drosophila larval neuromuscular junction (NMJ) with voltage-clamp recordings. Our data showed that both currents were generally unaffected by loss-of-function or Alzheimer’s disease (AD) -associated presenilin mutations under normal or stress conditions induced by heat shock (HS) or ER stress. In larvae expressing the mutant presenilins, prolonged Ca²⁺ tail current, reflecting slower deactivation kinetics of Ca²⁺ channels, was observed 1 day after stress treatments were terminated. It was further demonstrated that the L-type Ca²⁺ channel was specifically affected under these conditions. Moreover, synaptic plasticity at the NMJ was reduced in larvae expressing the mutant presenilins. At the behavioral level, memory in adult flies was impaired in the presenilin mutants 1 day after HS. The results show that presenilin function is important during the poststress period and its impairment contributes to memory dysfunction observed during adaptation to normal conditions after stress. Our findings suggest a new stress-related mechanism by which presenilin may be implicated in the neuropathology of AD.--Lu, Y., Lv, Y., Ye, Y., Wang, Y., Hong, Y., Fortini, M. E., Zhong, Y., Xie, Z. A role for presenilin in post-stress regulation: effects of presenilin mutations on Ca²⁺ currents in Drosophila.