Synaptic homeostats: latent plasticity revealed at the Drosophila neuromuscular junction

Homeostatic signaling systems are fundamental forms of biological regulation that maintain stable functionality in a changing environment. In the nervous system, synapses are crucial substrates for homeostatic modulation, serving to establish, maintain, and modify the balance of excitation and inhibition. Synapses must be sufficiently flexible to enable the plasticity required for learning and memory but also endowed with the stability to last a lifetime. In response to the processes of development, growth, remodeling, aging, and disease that challenge synapses, latent forms of adaptive plasticity become activated to maintain synaptic stability. In recent years, new insights into the homeostatic control of synaptic function have been achieved using the powerful Drosophila neuromuscular junction (NMJ). This review will focus on work over the past 10 years that has illuminated the cellular and molecular mechanisms of five homeostats that operate at the fly NMJ. These homeostats adapt to loss of postsynaptic neurotransmitter receptor functionality, glutamate imbalance, axonal injury, as well as aberrant synaptic growth and target innervation. These diverse homeostats work independently yet can be simultaneously expressed to balance neurotransmission. Growing evidence from this model glutamatergic synapse suggests these ancient homeostatic signaling systems emerged early in evolution and are fundamental forms of plasticity that also function to stabilize mammalian cholinergic NMJs and glutamatergic central synapses.