Homeostatic Synaptic Depression is Achieved Through a Regulated 1 Decrease in Presynaptic Calcium Channel Abundance

Acknowledgements: The authors declare no competing financial interests. We thank 29 Özgür Genç and TingTing Wang for comments on the manuscript. ABSTRACT 33 Homeostatic signaling stabilizes synaptic transmission at the neuromuscular 34 junction (NMJ) of Drosophila, mice, and human. It is believed that homeostatic 35 signaling at the NMJ is bi-directional and considerable progress has been made 36 identifying mechanisms underlying the homeostatic potentiation of 37 neurotransmitter release. However, very little is understood mechanistically about 38 the opposing process, homeostatic depression, and how bi-directional plasticity is 39 achieved. Here we show that homeostatic potentiation and depression can be 40 simultaneously induced, demonstrating true bi-directional plasticity. Next, we 41 show that mutations that block homeostatic potentiation do not alter homeostatic 42 depression, demonstrating that these are genetically separable processes. Finally, 43 we show that homeostatic depression is achieved by decreased presynaptic 44 calcium channel abundance and calcium influx, changes that are independent of 45 the presynaptic action potential waveform. Thus, we identify a novel mechanism 46 of homeostatic synaptic plasticity and propose a model that can account for the 47 observed bi-directional, homeostatic control of presynaptic neurotransmitter 48