Homeostatic Presynaptic Plasticity Is Specifically Regulated by P/Q-type Ca 2+ Channels at Mammalian Hippocampal Synapses

Abstract

SummaryVoltage-dependent Ca2+ channels (VGCC) represent the principal source of Ca2+ ions driving evoked neurotransmitter release at presynaptic boutons. In mammals, presynaptic Ca2+ influx is mediated mainly via P/Q-type and N-type VGCC, which differ in their properties. Changes in their relative contributions tune neurotransmission both during development and in Hebbian plasticity. However, whether this represents a functional motif also present in other forms of activity-dependent regulation is unknown. Here, we study the role of VGCC in homeostatic plasticity (HSP) in mammalian hippocampal neurons using optical techniques. We find that changes in evoked Ca2+ currents specifically through P/Q-type, but not N-type, VGCC mediate bidirectional homeostatic regulation of both neurotransmitter release efficacy and the size of the major synaptic vesicle pools. Selective dependence of HSP on P/Q-type VGCC in mammalian terminals has important implications for phenotypes associated with P/Q-type channelopathies, including migraine and epilepsy.

Homeostatic control of Drosophila neuromuscular junction function

“…There are relevant parallels to vertebrate models. At mouse hippocampal synapses, prolonged elevation of neural activity upon Gabazine treatment induces a homeostatic decrease in presynaptic Ca 2+ influx and release (Jeans et al, 2017;Zhao et al, 2011), which is mediated by the activity of Ca V 2.1 (P/Q)-type Ca 2+ channels (Jeans et al, 2017). There is also evidence for a homeostatic reduction of neurotransmitter release after prolonged depolarization at hippocampal synapses (Moulder, Jiang, Taylor, Olney, & Mennerick, 2006).…”

“…For chronic challenges to synapse function, there are some indications for conserved homeostatic mechanisms. These responses include retrograde signaling mediated by TOR (Henry et al, 2012), a requirement for presynaptic Ca 2+ -channel activity to effect potentiation (Jakawich et al, 2010), as well as changes in presynaptic Ca 2+ influx that offset various perturbations (Zhao et al, 2011) or vesicle pool size (Jeans et al, 2017;Kim & Ryan, 2010). Less is known about the conservation of rapid forms of homeostatic plasticity.…”

Rapid and Sustained Homeostatic Control of Presynaptic Exocytosis at a Central Synapse

“…The expression of PHP depends on cell-culture age, with cultures older than two weeks compensating for prolonged activity deprivation through concomitant regulation of 20 presynaptic release, postsynaptic receptor abundance, and synapse number (19)(20)(21)(22). Despite evidence for compensatory changes in presynaptic structure and function (23)(24)(25)(26)(27), it is currently not well understood how these relate to the postsynaptic modifications during synaptic scaling. Moreover, it has remained largely elusive if PHP stabilizes the activity of native neural circuits (8,28,29).…”

“…Homeostatic pr changes have been described for the Drosophila NMJ (65,66) and in mammalian CNS cell culture (20,27), suggesting evolutionary conservation. A major factor that has been linked to homeostatic pr control is the modulation of presynaptic Ca 2+ influx (24,65).…”

“…At the Drosophila NMJ, genetic data suggests that distinct molecular pathways underlie homeostatic modulation of RRP and Ca 2+ influx/pr (64). There is recent evidence that homeostatic vesicle pool regulation requires altered Ca 2+ influx 20 through P/Q-type Ca 2+ channels at cultured mammalian synapses (24). By contrast, PHP at the mouse NMJ involves RRP modulation without any evidence for changes in pr (18).…”