Homeostatic Depression Shows Heightened Sensitivity to Synaptic Calcium.

Catherine J Yeates,C Andrew Frank

doi:10.3389/fncel.2021.618393

Abstract

Synapses and circuits rely on homeostatic forms of regulation in order to transmit meaningful information. The Drosophila melanogaster neuromuscular junction (NMJ) is a well-studied synapse that shows robust homeostatic control of function. Most prior studies of homeostatic plasticity at the NMJ have centered on presynaptic homeostatic potentiation (PHP). PHP happens when postsynaptic muscle neurotransmitter receptors are impaired, triggering retrograde signaling that causes an increase in presynaptic neurotransmitter release. As a result, normal levels of evoked excitation are maintained. The counterpart to PHP at the NMJ is presynaptic homeostatic depression (PHD). Overexpression of the Drosophila vesicular glutamate transporter (VGlut) causes an increase in the amplitude of spontaneous events. PHD happens when the synapse responds to the challenge by decreasing quantal content (QC) during evoked neurotransmissionagain, resulting in normal levels of postsynaptic excitation. We hypothesized that there may exist a class of molecules that affects both PHP and PHD. Impairment of any such molecule could hurt a synapses ability to respond to any significant homeostatic challenge. We conducted an electrophysiology-based screen for blocks of PHD. We did not observe a block of PHD in the genetic conditions screened, but we found loss-of-function conditions that led to a substantial deficit in evoked amplitude when combined with VGlut overexpression. The conditions causing this phenotype included a double heterozygous loss-of-function condition for genes encoding the inositol trisphosphate receptor (IP3R itpr) and ryanodine receptor (RyR). IP3Rs and RyRs gate calcium release from intracellular stores. Pharmacological agents targeting IP3R and RyR recapitulated the genetic losses of these factors, as did lowering calcium levels from other sources. Our data are consistent with the idea that the homeostatic signaling process underlying PHD is especially sensitive to levels of calcium at the presynapse.

Highlights

Animal nervous systems use forms of homeostatic synaptic plasticity to maintain stable function
Our results suggest that impairing store calcium channels may result in a cumulative defect in neurotransmission when there is a concurrent presynaptic homeostatic depression (PHD) challenge
excitatory postsynaptic potential (EPSP) were significantly reduced (Figures 6C, middle, 6D) because of a marked decrease in quantal content (Figure 6C, right). Taking all of these data together, for each case where we examined a dual impairment of ryanodine receptor (RyR) and IP3 receptors (IP3Rs) the EPSP amplitudes were all quite low with concomitant vesicular glutamate transporter (VGlut) overexpression (Figures 3–6)

Summary

Introduction

Animal nervous systems use forms of homeostatic synaptic plasticity to maintain stable function. Much of the NMJ homeostasis work in both Drosophila and vertebrates has focused on a form of homeostatic plasticity termed presynaptic homeostatic potentiation (PHP). With PHP, manipulations that impair postsynaptic muscle receptor function trigger an increase in presynaptic vesicle release (Cull-Candy et al, 1980; Petersen et al, 1997; Davis et al, 1998; Frank et al, 2006; Wang et al, 2016). PHP is reversible—when manipulations that impair muscle receptor function are removed, the presynaptic potentiation ceases (Wang et al, 2016; Yeates et al, 2017). The Drosophila NMJ can depress quantal content (QC) in a homeostatic manner functionally opposite to PHP: presynaptic homeostatic depression (PHD). To compensate for this, quantal content at the NMJ is lowered, resulting in normal evoked postsynaptic excitation (Daniels et al, 2004)

Methods

Results

Conclusion