Autocrine inhibition by a glutamate-gated chloride channel mediates presynaptic homeostatic depression

Homeostatic modulation of presynaptic neurotransmitter release is a fundamental form of plasticity that stabilizes neural activity, where presynaptic homeostatic depression (PHD) can adaptively diminish synaptic strength. PHD has been proposed to operate through an autocrine mechanism to homeostatically depress release probability in response to excess glutamate release at the Drosophila neuromuscular junction. This model implies the existence of a presynaptic glutamate autoreceptor. We systematically screened all neuronal glutamate receptors in the fly genome and identified the glutamate-gated chloride channel (GluCl alpha) to be required for the expression of PHD. Pharmacological, genetic, and Ca2+ imaging experiments demonstrate that GluCl alpha acts locally at axonal terminals to drive PHD. Unexpectedly, GluCl alpha localizes and traffics with synaptic vesicles to drive presynaptic inhibition through an activity-dependent anionic conductance. Thus, GluCl alpha operates as both a sensor and effector of PHD to adaptively depress neurotransmitter release through an elegant autocrine inhibitory signaling mechanism at presynaptic terminals.

Automated summary

The study revealed that the Glutamate-gated chloride channel (GluCl alpha) in Drosophila neurons plays a critical role in presynaptic homeostatic depression (PHD), driving the process through an activity-dependent anionic conductance.