Homeostatic plasticity at the Drosophila neuromuscular junction

Abstract

In biology, homeostasis refers to how cells maintain appropriate levels of activity. This concept underlies a balancing act in the nervous system. Synapses require flexibility (i.e. plasticity) to adjust to environmental challenges. Yet there must also exist regulatory mechanisms that constrain activity within appropriate physiological ranges. An abundance of evidence suggests that homeostatic regulation is critical in this regard. In recent years, important progress has been made towards identifying molecules and signaling processes required for homeostatic forms of neuroplasticity. The Drosophila melanogaster third instar larval neuromuscular junction (NMJ) has been an important experimental system in this effort. Drosophila neuroscientists combine genetics, pharmacology, electrophysiology, imaging, and a variety of molecular techniques to understand how homeostatic signaling mechanisms take shape at the synapse. At the NMJ, homeostatic signaling mechanisms couple retrograde (muscle-to-nerve) signaling with changes in presynaptic calcium influx, changes in the dynamics of the readily releasable vesicle pool, and ultimately, changes in presynaptic neurotransmitter release. Roles in these processes have been demonstrated for several molecules and signaling systems discussed here. This review focuses primarily on electrophysiological studies or data. In particular, attention is devoted to understanding what happens when NMJ function is challenged (usually through glutamate receptor inhibition) and the resulting homeostatic responses. A significant area of study not covered in this review, for the sake of simplicity, is the homeostatic control of synapse growth, which naturally, could also impinge upon synapse function in myriad ways.

Transmission, Development, and Plasticity of Synapses

“…Whether acute and developmental homeostatic changes are regulated by the same mechanisms is still unclear. Current findings support overlapping but nonidentical regulation of these two modes of plasticity (see Frank 2014). A recent forward-genetic screen used PhTx application to identify mutations that block acute homeostatic compensation (Dickman and Davis 2009;Müller et al 2011;Younger et al 2013).…”

“…To specifically impede miniature neurotransmission, Choi et al (2014) compared iGluR mutants expressing either a functional (iGluR WT ) or nonfunctional (iGluR MUT ) rescue transgene. These animals have comparable evoked neurotransmission, due to homeostatic compensation of quantal content in the iGluR MUT animals (see Frank 2014 and Homeostatic Plasticity section of this review). However, iGluR MUT animals have severely reduced miniature neurotransmission that is accompanied by a strong reduction in bouton size.…”

“…Homeostatic plasticity of synapses has been shown in a variety of animal models to include changes in excitability, regulation of neurotransmitter release, or regulation of postsynaptic neurotransmitter receptors. The molecular pathways that contribute to homeostatic plasticity in Drosophila NMJ and other systems has been recently reviewed (Davis 2013;Davis and Müller 2014;Frank 2014). We will briefly discuss some key findings below.…”

Mechanisms controlling neuromuscular junction stability

“…Anyway, among answers to retrograde signaling that have already been demonstrated to be involved in homeostatic plasticity and compensation at the NMJ, in Drosophila in particular, are the size of readily releasable pool of synaptic vesicles and pre-synaptic calcium influx. It can occur through the post-synaptic inhibition of glutamate receptors, the impairment of muscle excitability, or through the alteration of the rates of innervation received by individual muscles, for Drosophila NMJ in particular as demonstrated through the use of fasciclin mutants (reviewed in [22]). It will be important to demonstrate the cues that are involved in synaptic homeostasis challenges, in addition to modulation of AchR density [23] during normal development and mono-innervation acquisition in mammalian central and peripheral synapses, but also in human health and pathophysiology.…”

Emerging Trends in Retrograde Signaling

“…Earlier studies showed that the muscle-derived BMP ligand glassbottom boat (Gbb) and its presynaptic receptor wishful thinking (Wit) via retrograde axonal transport to activate the Drosophila Mad (Smad) transcription factor are needed for both rapid (PhTx) and long-term (GluRIIA mutant) forms of synaptic homeostasis. But, current data suggest a permissive rather than an instructive role for BMP/Mad signaling during rapid homeostatic compensation and further studies to certify the systems' role are required [49].…”