Cellular bases of activity‐dependent paralysis in Drosophila stress‐sensitive mutants

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Abstract
Stress‐sensitive mutants in Drosophila have been shown to exhibit activity‐dependent defects in neurotransmission. Using the neuromuscular junction (NMJ), this study investigates synaptic function more specifically in two stress‐sensitive mutants: stress‐sensitive B (sesB), which encodes a mitochondrial ADP/ATP translocase (ANT); and Atpα2206, a conditional mutant of the Na+/K+ ATPase α‐subunit. Mechanical shock induces a period of brief paralysis in both homozygous and double heterozygous mutants, but further analysis revealed distinct activity‐dependent neurotransmission lesions in each mutant. Basal neurotransmission appeared similar to wild‐type controls in both mutants under low frequency stimulation. High frequency stimulation, however, caused pronounced synaptic fatigue as well as slow and incomplete synaptic recovery in sesB mutants while Atpα2206 mutants displayed an increase (25‐fold) in synaptic failures. Perhaps to compensate for these activity dependent defects, the neuromuscular synapse was found to be overgrown in both mutants. Passive electrotonic stimulation, which initiates synaptic transmission independent of action potentials, ameliorated synaptic failures and resulted in increased neurotransmission amplitude in Atpα2206 mutants. In addition, spontaneous synaptic vesicle fusion rates were increased in Atpα2206 mutants, suggesting that, in the absence of action potential requirements, these synaptic terminals are healthy, if not hyperactive. Dye labeling studies revealed aberrant synaptic vesicle cycling in sesB mutants indicating a reduction of functional synaptic vesicles. We therefore postulate that both stress‐sensitive mutants harbor unique neurotransmission defects: Atpα2206 mutants are unable to maintain ionic gradients required during repetitive action potential propagation, and sesB mutants cannot maintain synaptic vesicle cycling during periods of high demand. © 2004 Wiley Periodicals, Inc. J Neurobiol 60:328–347, 2004