Abstract
Presynaptic homeostatic plasticity (PHP) compensates for impaired postsynaptic neurotransmitter receptor function through a rapid, persistent adjustment of neurotransmitter release, an effect that can exceed 200%. An unexplained property of PHP is the preservation of short-term plasticity (STP), thereby stabilizing activity-dependent synaptic information transfer. We demonstrate that the dramatic potentiation of presynaptic release during PHP is achieved while simultaneously maintaining a constant ratio of primed to super-primed synaptic vesicles, thereby preserving STP. Mechanistically, genetic, biochemical and electrophysiological evidence argue that a constant ratio of primed to super-primed synaptic vesicles is achieved by the concerted action of three proteins: Unc18, Syntaxin1A and RIM. Our data support a model based on the regulated availability of Unc18 at the presynaptic active zone, a process that is restrained by Syntaxin1A and facilitated by RIM. As such, regulated vesicle priming/super-priming enables PHP to stabilize both synaptic gain and the activity-dependent transfer of information at a synapse.
Highlights
Based upon these and other data, we present a new model for the homeostatic control of synaptic vesicle release that is based upon the regulated control of Unc18 levels at the presynaptic release site, acting in concert with the priming activity of RIM to stabilize short-term plasticity (STP) in the presence of a homeostatic doubling presynaptic neurotransmitter release
PhTx causes a ~ 50% decrease in miniature excitatory postsynaptic potential amplitude and induces a homeostatic increase in presynaptic vesicle release that precisely counteracts the change in mEPSP amplitude, maintaining the amplitude of action potential evoked neurotransmitter release
We characterize the expression of STP at two concentrations of external calcium (0.75 mM and 3.0 mM [Ca2+]e), doing so in the presence and absence of PhTx to induce Presynaptic homeostatic plasticity (PHP) (Figure 1A–C)
Summary
Presynaptic homeostatic plasticity (PHP) is an evolutionarily conserved form of homeostatic control that is expressed in organisms ranging from fly to human (Cull-Candy et al, 1980; Plomp et al, 1992; Davis, 2013; Wang et al, 2011), at both central and peripheral synapses (Liu and Tsien, 1995; Davis and Goodman, 1998; Burrone et al, 2002; Thiagarajan et al, 2005; Kim and Ryan, 2010; Zhao et al, 2011; Davis, 2013; Henry et al, 2012; Jakawich et al, 2010). The fact that STP is held constant during the expression of PHP may be essential to the life-long stabilization of neural circuit function and animal behavior It remains fundamentally unknown how presynaptic release can be rapidly doubled at a fixed number of active zones while maintaining constant short-term release dynamics. We show that Unc function during PHP is facilitated by the activity of presynaptic RIM and, remarkably, is antagonized by presynaptic Syntaxin Based upon these and other data, we present a new model for the homeostatic control of synaptic vesicle release that is based upon the regulated control of Unc levels at the presynaptic release site, acting in concert with the priming activity of RIM to stabilize STP in the presence of a homeostatic doubling presynaptic neurotransmitter release
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