Effects of oxidative stress and aging on nerve, muscle, and synapse in a male-specific abdominal neuromuscular junction in Drosophila

Defects in Drosophila Cu2+/Zn2+ superoxide dismutase (encoded by the gene Sod1) lead to elevated oxidative stress and a drastically shortened lifespan. To determine the effects of aging and oxidative stress on nerve conduction, synaptic transmission, and muscle excitability, we developed an easily accessible adult abdominal neuromuscular preparation, utilizing the male-specific Muscle of Lawrence (MOL) in Drosophila. The large size of MOL facilitated analyses of presynaptic nerve signals and postsynaptic responses that could initiate sizable excitatory junctional potentials (EJPs) to evoke a full-blown muscle action potential (AP) terminated rapidly by a characteristic afterhyperpolarization (AHP). Aged wild-type (WT) individuals (80 days or older) exhibited diminished neuromuscular transmission, mainly reflecting declines in motor axon conduction, with synaptic transmission largely intact (since robust EJPs remained when nerve terminals stimulated electrotonically). Additionally, muscle APs showed enhanced depolarization and weakened AHP during current injection. Chronologically younger Sod1 mutants (up to 30 days) displayed similar trends of neuromuscular changes, confirming a major role of oxidative stress in aging. However, certain distinctions exist in muscle membrane properties and transmitter release machinery. A clear increase in MOL membrane resistance was seen in Sod1 but not in aged WT. Additionally, a striking, extremely enlarged spontaneous transmitter release (mEJPs) occurred in aged WT but was never seen in Sod1, indicating a distinct effect of aging on transmitter release regulation. Notably, these alterations showed considerable variation among individuals, ranging from transmission failure to nearly intact neuromuscular functions, demonstrating the stochastic nature in aging- and oxidative stress-related functional declines. Moreover, this study uncovered a well-defined vulnerability to aging and oxidative stress that involves weakening of the Ca2+-activated BK current, causing drastic reduction in AHP in both aged WT and Sod1 mutants, as confirmed by their diminishing sensitivity to the BK channel blocker paxilline.

Ueda, A., Wu, C.-F.

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