Abstract
The homeostatic modulation of neurotransmitter release, termed presynaptic homeostatic potentiation (PHP), is a fundamental type of neuromodulation, conserved from Drosophila to humans, that stabilizesinformation 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.
Highlights
Presynaptic homeostatic potentiation (PHP) can be initiated by disruption of postsynaptic neurotransmitter receptors and is expressed as a change in presynaptic vesicle release (Davis, 2006, 2013; Davis and Mu€ller, 2015)
When we assay the rapid induction of presynaptic homeostatic potentiation (PHP), we find that application of PhTX caused a significant reduction of miniature excitatory postsynaptic potential amplitudes (mEPSPs) amplitude in all genotypes (Figures 1B, 1C, S1, and S2)
The magnitude of homeostatic compensation in this double heterozygous mutant is not significantly different than either wild-type or the heterozygous mutations alone (Figure 7B; p > 0.05, one-way ANOVA, Bonferroni’s test). These data argue for the specificity of the genetic interaction between rim and a2d-3 and support the possibility that a2d-3 may relay signaling from the synaptic cleft to Rab3-interacting molecule (RIM) during presynaptic homeostasis
Summary
The homeostatic control of neurotransmitter release stabilizes information transfer at synaptic connections throughout the nervous system. Wang et al find that a calcium channel auxiliary subunit (a2d-3) is required for homeostatic synaptic plasticity. The a2d gene family has been linked to neurological disease and two psychiatric drugs, gabapentin and pregabalin. 2016, Cell Reports 16, 2875–2888 September 13, 2016 a 2016 The Authors.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
