The calcineurin regulator Sarah enables distinct forms of homeostatic plasticity at theDrosophilaneuromuscular junction

Abstract

The ability of synapses to maintain physiological levels of evoked neurotransmission is essential for neuronal stability. A variety of perturbations can disrupt neurotransmission, but synapses often compensate for disruptions and work to stabilize activity levels, using forms of homeostatic synaptic plasticity. Presynaptic homeostatic potentiation (PHP) is one such mechanism that is expressed at the model Drosophila melanogaster larval neuromuscular junction (NMJ) synapse. In PHP, neurotransmitter release increases in response to challenges to the synapse, resulting in the maintenance of evoked neurotransmission. Prior work separated PHP into two temporal phases, acute and chronic. Those data suggested that cytoplasmic calcium signaling was important for a long-term maintenance of PHP. Here we used a combination of transgenic Drosophila RNA interference and overexpression lines, along with NMJ electrophysiology, synapse imaging, and pharmacology to test if regulators of the calcium/calmodulin-dependent protein phosphatase calcineurin are necessary for the normal expression of acute or chronic forms of PHP. We found that either pre- or postsynaptic dysregulation of a Drosophila gene regulating calcineurin, sarah (sra), blocks PHP. Examination of tissue-specific data showed that increases and decreases in sra expression are both detrimental to PHP. Additionally, the acute and chronic phases of PHP are functionally separable depending entirely upon which sra genetic manipulation is used. Surprisingly, concurrent pre- and postsynaptic sra knockdown or overexpression ameliorated PHP blocks revealed in single tissue experiments. Pharmacological inhibition of calcineurin corroborated this latter finding. Our results suggest that a discrete balance of calcineurin signaling is needed across multiple synapse tissue types and over different temporal phases to stabilize peripheral synaptic outputs.