Abstract
Presynaptic ligand-gated ion channels (LGICs) have long been proposed to affect neurotransmitter release and to tune the neural circuit activity. However, the understanding of their in vivo physiological action remains limited, partly due to the complexity in channel types and scarcity of genetic models. Here we report that C. elegans LGC-46, a member of the Cys-loop acetylcholine (ACh)-gated chloride (ACC) channel family, localizes to presynaptic terminals of cholinergic motor neurons and regulates synaptic vesicle (SV) release kinetics upon evoked release of acetylcholine. Loss of lgc-46 prolongs evoked release, without altering spontaneous activity. Conversely, a gain-of-function mutation of lgc-46 shortens evoked release to reduce synaptic transmission. This inhibition of presynaptic release requires the anion selectivity of LGC-46, and can ameliorate cholinergic over-excitation in a C. elegans model of excitation-inhibition imbalance. These data demonstrate a novel mechanism of presynaptic negative feedback in which an anion-selective LGIC acts as an auto-receptor to inhibit SV release.
Highlights
Cys-loop Ligand-gated ion channels (LGICs) participate in rapid regulation of neurotransmission by changing the plasma membrane conductance upon ligand binding (Keramidas et al, 2004)
This effect was blocked by picrotoxin, an antagonist of ionotropic GABA receptors, implying that GABAA receptors may be involved in inhibition of presynaptic release (Eccles et al, 1963)
Ultrastructural studies later revealed that the extensor afferent neuron terminals receive axoaxonal connections from GABAergic interneurons that are activated by flexor afferent neurons (Pierce and Mendell, 1993; Destombes et al, 1996), suggesting the presence of GABA-gated LGICs in presynaptic axons
Summary
Cys-loop Ligand-gated ion channels (LGICs) participate in rapid regulation of neurotransmission by changing the plasma membrane conductance upon ligand binding (Keramidas et al, 2004). Classical electrophysiological recordings from cat spinal cord showed that activation of flexor afferent neurons caused decreased excitatory transmission of extensor afferent neurons onto extensor motor neurons (Eccles et al, 1961, 1963; Frank and Fuortes, 1957). This effect was blocked by picrotoxin, an antagonist of ionotropic GABA receptors, implying that GABAA receptors may be involved in inhibition of presynaptic release (Eccles et al, 1963).
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