| First Author | Yang J | Year | 2019 |
| Journal | Neuron | PubMed ID | 30982627 |
| Mgi Jnum | J:273644 | Mgi Id | MGI:6294312 |
| Doi | 10.1016/j.neuron.2019.03.029 | Citation | Yang J, et al. (2019) Glutamate-Releasing SWELL1 Channel in Astrocytes Modulates Synaptic Transmission and Promotes Brain Damage in Stroke. Neuron |
| abstractText | By releasing glutamate, astrocytes actively regulate synaptic transmission and 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. |
