Synapse-specific and compartmentalized expression of presynaptic homeostatic potentiation

Abstract

Postsynaptic compartments can be specifically modulated during various forms of synaptic plasticity, but it is unclear whether this precision is shared at presynaptic terminals. Presynaptic homeostatic plasticity (PHP) stabilizes neurotransmission at the Drosophila neuromuscular junction, where a retrograde enhancement of presynaptic neurotransmitter release compensates for diminished postsynaptic receptor functionality. To test the specificity of PHP induction and expression, we have developed a genetic manipulation to reduce postsynaptic receptor expression at one of the two muscles innervated by a single motor neuron. We find that PHP can be induced and expressed at a subset of synapses, over both acute and chronic time scales, without influencing transmission at adjacent release sites. Further, homeostatic modulations to CaMKII, vesicle pools, and functional release sites are compartmentalized and do not spread to neighboring pre- or post-synaptic structures. Thus, both PHP induction and expression mechanisms are locally transmitted and restricted to specific synaptic compartments.

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

“…Previous work demonstrated that the fast expression of PHP in response to PhTx occurs even when the motor neuron axon is severed (Frank et al, 2006). Also, the signaling necessary for PHP expression is restricted to postsynaptic densities and presynaptic boutons (Li et al, 2018). Second, Neto-CTD, but not Neto-β, rescued the basal neurotransmission defects in neto-α null (Figures 6 and 8).…”

The sleep gene insomniac ubiquitinates targets at postsynaptic densities and is required for retrograde homeostatic signaling

“…Together, these results demonstrate that inc functions downstream of or in parallel to CaMKII in 224 the postsynaptic compartment, where it is necessary for the retrograde homeostatic signaling 225 that adaptively modulates presynaptic structure and neurotransmitter release (schematized in 226 Fig. 3)), suggesting that the key processes driving synapse-250 specific retrograde PHP signaling occur in this structure (Li et al, 2018b). We therefore first 251 determined whether Inc is present at the postsynaptic density.…”

Homeostatic control of Drosophila neuromuscular junction function

“…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.…”

“…Unc18 or GFP-tagged Cacophony (Gratz et al, 2019;Li, Goel, Chen, et al, 2018), implying a sustained increase in the levels of these proteins during PHP. In this case, three of the above-mentioned genes that have been tested for PHP in the GluRIIA SP16 mutant background-cacophony (Frank et al, 2006), Brp Penney et al, 2012), and Srpk79D ( (2019), Arl8-dependent structural plasticity was dispensable for rapid PHP expression, but required for sustained PHP expression.…”

“…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).…”