Disparate Postsynaptic Induction Mechanisms Ultimately Converge to Drive the Retrograde Enhancement of Presynaptic Efficacy

Abstract

SUMMARY Retrograde signaling systems are fundamental modes of communication that synapses utilize to dynamically and adaptively modulate activity. However, the inductive mechanisms that gate retrograde communication in the postsynaptic compartment remain enigmatic. We have investigated retrograde signaling at the Drosophila neuromuscular junction, where three seemingly disparate perturbations to the postsynaptic cell trigger a similar enhancement in presynaptic neurotransmitter release. We show that the same presynaptic genetic machinery and enhancements in active zone structure are utilized by each inductive pathway. However, all three induction mechanisms differ in temporal, translational, and CamKII activity requirements to initiate retrograde signaling in the postsynaptic cell. Intriguingly, pharmacological blockade of postsynaptic glutamate receptors, and not calcium influx through these receptors, is necessary and sufficient to induce rapid retrograde homeostatic signaling through CamKII. Thus, three distinct induction mechanisms converge on the same retrograde signaling system to drive the homeostatic strengthening of presynaptic neurotransmitter release.

Homeostatic control of Drosophila neuromuscular junction function

“…Recently, it was found that postsynaptic glutamate receptor inhibition and postsynaptic mTOR overexpression enhance release through similar presynaptic mechanisms (Figure 3a; Goel et al, 2017). However, while postsynaptic glutamate receptor impairment resulted in decreased pCaMKII levels, this was not observed after postsynaptic mTOR overexpression (Goel et al, 2017). This indicates that postsynaptic glutamate receptor impairment and mTOR signaling likely control presynaptic release through different pathways.…”

“…Retrograde PHP signaling involves multiplexin/ endostatin (Wang et al, 2014) and Sema-2B/Plexin B (Orr et al, 2017). PHP requires postsynaptic mTOR signaling (Goel et al, 2017;Penney et al, 2012), class II PI3 kinase function (Hauswirth et al, 2018), and reduced pCaMKII levels (Goel et al, 2017;Li, Goel, Chen, et al, 2018;Newman et al, 2017). Note that the cartoon only summarizes recent genes implicated in PHP.…”

“…Several lines of evidence suggest a regulatory role of postsynaptic CaMKII in PHP (Figure 3a): Postsynaptic expression of a constitutively active CaMKII transgene impairs long-term PHP expression Li, Goel, Chen, et al, 2018). Two groups recently reported a decreased phosphorylation state of CaMKII (pCaMKII) in the muscle cell upon long-term glutamate receptor perturbation (Goel et al, 2017;Li, Goel, Chen, et al, 2018;Newman et al, 2017; see Section 2.2. above). PHP can be induced in the absence of extracellular Ca 2+ (Goel et al, 2017), and the decrease in pCaMKII levels after glutamate receptor inhibition occurs in the absence of extracellular Ca 2+ (Goel et al, 2017).…”

“…Further studies have demonstrated postsynaptic roles for a discrete set of molecules in PHP expression, including canonical BMP signaling components (Goold & Davis, 2007), a regulatory network of Src-family tyrosine kinases (Spring, Brusich, & Frank, 2016), as well as the Drosophila homologs of proteins known to regulate cap-dependent translation, target of rapamycin (TOR), S6 kinase (S6K), eIF43, and 4E-BP (Kauwe et al, 2016;Penney et al, 2012). Recently, it was found that postsynaptic glutamate receptor inhibition and postsynaptic mTOR overexpression enhance release through similar presynaptic mechanisms (Figure 3a; Goel et al, 2017). However, while postsynaptic glutamate receptor impairment resulted in decreased pCaMKII levels, this was not observed after postsynaptic mTOR overexpression (Goel et al, 2017).…”

Neto-α controls synapse organization and homeostasis at the Drosophila neuromuscular junction

“…Previous studies demonstrated that PhTx application results in a rapid increase in the quantity of presynaptic active zone protein Brp, accompanied by an elaboration of the presynaptic cytomatrix structure (Goel et al, 2017;Weyhersmuller et al, 2011). We visualized and quantified the Brp puncta before and after PhTx exposure by confocal microscopy (see Materials and Methods).…”