α2δ-3 Is Required for Rapid Transsynaptic Homeostatic Signaling

Abstract

The homeostatic modulation of neurotransmitter release, termed presynaptic homeostatic potentiation (PHP), is a fundamental type of neuromodulation, conserved from Drosophila to human, that stabilizes information transfer at synaptic connections throughout the nervous system. Here we demonstrate that α2δ-3, an auxiliary subunit of the presynaptic calcium channel, is required for PHP. The α2δ gene family has been linked to chronic pain, epilepsy, autism and the action of two psychiatric drugs, gabapentin and pregabalin. We demonstrate that loss of α2δ-3 blocks both the rapid induction and sustained expression of PHP due to a failure to potentiate presynaptic calcium influx and the RIM-dependent readily-releasable vesicle pool. These deficits are independent of α2δ-3-mediated regulation of baseline calcium influx and presynaptic action potential waveform. α2δ proteins reside at the extracellular face of presynaptic release sites throughout the nervous system, an ideal site to mediate rapid, trans-synaptic homeostatic signaling in health and disease.

Retrograde semaphorin–plexin signalling drives homeostatic synaptic plasticity

“…In blue, two components residing in the synaptic extracellular matrix have been implicated in PHP. The α2δ3 auxiliary subunit of the presynaptic calcium channel is necessary for PHP 36 . The matrix-derived signaling protein Endostatin, a cleavage product of the collagen homologue Multiplexin, is also necessary for PHP 37 .…”

Different α2δ Accessory Subunits Regulate Distinctly Different Aspects of Calcium Channel Function in the Same Drosophila Neurons

“…Notably, in Drosophila motoneurons both dα 2 δ 1 and dα 2 δ 3 are co-expressed, but localize to different subneuronal compartments. dα 2 δ 3 but not dα 2 δ 1 localizes at axon terminals and is required for presynaptic function (Wang et al, 2016; this study) and embryonic synapse development (Kurshan et al, 2009). Moreover, we find that dα 2 δ 3 and dα 2 δ 1 affect different aspects of motoneuron calcium channel function (see below) .…”

“…During embryonic development loss of dα 2 δ 3 (stj) function impairs early steps of synapse formation before calcium channels arrive at the presynaptic terminal, as well as the subsequent recruitment of Ca v 2-like channels to the active zone (Kurshan et al, 2009). Moreover, at mature larval neuromuscular junctions, dα 2 δ 3 is required for rapid induction and continuous expression of pre-synaptic homeostatic potentiation (Wang et al, 2016). Our data demonstrate that dα 2 δ 3 is not only required for Ca v 2 channel function at the pre-synaptic terminal, but also for normal flight motoneuron somatodendritic and axonal calcium currents, both of which are mediated by the Drosophila Ca v 2 channel homolog cacophony .…”

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

“…Besides Brp, several presynaptic components have been implicated in the control of PHP (reviewed in (Frank, 2014)). They include (1) Cacophony, the α1 subunit of CaV2-type calcium channels and its auxiliary protein α2-3, which control the presynaptic Ca 2+ influx Wang et al, 2016), (Letts et al) the signaling molecules upstream Cac, Eph, Ephexin and Cdc42 (Frank et al, 2009), and (3) the BMP pathway components, Wit and Mad, required for the retrograde BMP signaling (Goold and Davis, 2007). In addition, expression of PHP requires molecules that regulate vesicle release and the RRP size, such as RIM , Rab3-GAP (Muller et al, 2011), Dysbindin (Dickman and Davis, 2009), SNAP25 and Snapin (Dickman et al, 2012).…”