α2δ-3 Is Required for Rapid Transsynaptic Homeostatic Signaling

The homeostatic modulation of neurotransmitter release, termed presynaptic homeostatic potentiation (PHP), is a fundamental type of neuromodulation, conserved from Drosophila to humans, 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, a site ideal for mediating rapid, transsynaptic homeostatic signaling in health and disease. [Display omitted] •α2δ-3 is required for presynaptic homeostatic plasticity•α2δ-3 is necessary for the homeostatic modulation of presynaptic calcium influx•α2δ-3 controls the homeostatic modulation of the readily releasable vesicle pool•α2δ-3 is needed for acute induction and sustained expression of homeostatic plasticity The homeostatic control of neurotransmitter release stabilizes information transfer at synaptic connections throughout the nervous system. Wang et al. now find that a calcium channel auxiliary subunit (α2δ-3) is required for homeostatic synaptic plasticity. The α2δ gene family has been linked to neurological disease and two psychiatric drugs, gabapentin and pregabalin.