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Abstract

Once synapses have formed, functionally important connections have to be maintained and stabilized, mostly by transsynaptic adhesion complexes that are anchored in the underlying cytoskeleton. The Drosophila neuromuscular junction (NMJ) serves as a model system for central synapses in the vertebrate brain, as both synapse types share molecular and structural features. In a mutagenesis screen for regulators of synaptic stability, we recovered mutations in Drosophila ankyrin 2 (ank2) affecting two giant Ank2 isoforms that are specifically expressed in the nervous system, and that are tightly associated with the presynaptic membrane cytoskeleton. ank2 mutant larvae show severe deficits in the stability of NMJs, resulting in a reduction in overall terminal size. Synaptic boutons are withdrawn and presynaptic active zones are disassembled. In addition, lack of Ank2 leads to disintegration of the synaptic microtubule cytoskeleton. Microtubules and microtubule-associated proteins fail to extend into distant boutons. Interestingly, Ank2 functions downstream of Spectrin in the anchorage of synaptic microtubules, providing a cytoskeletal scaffold that is essential for synaptic stability.