α2δ-3 Is Required for Rapid Transsynaptic Homeostatic Signaling

• Main Authors: Tingting Wang, Ryan T. Jones, Jenna M. Whippen, Graeme W. Davis
• Format: Article
• Language: English
• Published: Elsevier 2016-09-01
• Series: Cell Reports
• Subjects: α2δ-3; calcium channel; CaV2.1; presynaptic calcium influx; readily releasable vesicle pool; homeostatic plasticity; synaptic homeostasis; synaptic transmission; neuromuscular junction; epilepsy; autism; neuropathic pain; schizophrenia
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124716310944

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.