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Abstract
By releasing glutamate, astrocytes actively regulate synaptic
transmission and also contribute to excitotoxicity in neurological diseases.
However, the mechanisms of astrocytic glutamate release have been debated. Here,
we report non-vesicular release of glutamate through the glutamate-permeable
volume-regulated anion channel (VRAC). Both cell swelling and receptor
stimulation activated astrocytic VRAC, which requires its only obligatory
subunit, Swell1. Astrocyte-specific Swell1 knockout mice
exhibited impaired glutamatergic transmission due to the decreases in
presynaptic release probability and ambient glutamate level. Consistently, the
mutant mice displayed hippocampal-dependent learning and memory deficits. During
pathological cell swelling, deletion of astrocytic Swell1 attenuated
glutamate-dependent neuronal excitability and protected mice from brain damage
after ischemic stroke. Our identification of a new molecular mechanism for
channel-mediated glutamate release establishes a role for astrocyte-neuron
interactions in both synaptic transmission and brain ischemia. It provides a
rationale for targeting VRAC for the treatment of stroke and other neurological
diseases associated with excitotoxicity. Whether and how astrocytes release glutamate
to regulate neuronal
function are debated. Yang et al. show that Swell1 volume-regulated anion
channel is a glutamate-releasing channel in astrocytes, which regulates basal
synaptic transmission and contributes to excitotoxicity in ischemic stroke.