TY - JOUR
T1 - Glutamate-Releasing SWELL1 Channel in Astrocytes Modulates Synaptic Transmission and Promotes Brain Damage in Stroke
AU - Yang, Junhua
AU - Vitery, Maria del Carmen
AU - Chen, Jianan
AU - Osei-Owusu, James
AU - Chu, Jiachen
AU - Qiu, Zhaozhu
N1 - Funding Information:
We thank Ardem Patapoutian for his invaluable support of the generation of conditional Swell1 mice; Woo-Ping Ge for helpful discussion; Xiang Shi, Siqi Zhao, Feng Yan, and Sai Yang for assistance with stroke model; Senthilkumar Karuppagounder for assistance with glutamate measurement; Stephen Traynelis for GluR1-L497Y plasmid; and Marie Hardwick for NEX-cre mice from Klaus-Armin Nave's laboratory. This work was supported by a grant from the NIH (R35 GM124824 to Z.Q.); AHA fellowships 19POST34410020 (J.Chen) and 18PRE34060025 (J.O.-O.); NIH fellowship F31 NS108658 (M.d.C.V.); and Johns Hopkins University School of Medicine. This paper is dedicated to the memory of our dear friend and wonderful colleague, Maria del Carmen Vitery, who recently passed away. J.Y. performed all electrophysiological experiments and in situ hybridization. M.d.C.V. and J.Y. performed behavior assays and immunostainings. J.Chen performed stroke model. J.Y. M.d.C.V. J.O.-O. J.Chu, and Z.Q. generated and characterized the knockout mouse models. J.Y. M.d.C.V. and J.Chen collected and analyzed data. Z.Q. and J.Y. designed the study and wrote the paper with input from all authors. The authors declare no competing interests.
Funding Information:
We thank Ardem Patapoutian for his invaluable support of the generation of conditional Swell1 mice; Woo-Ping Ge for helpful discussion; Xiang Shi, Siqi Zhao, Feng Yan, and Sai Yang for assistance with stroke model; Senthilkumar Karuppagounder for assistance with glutamate measurement; Stephen Traynelis for GluR1-L497Y plasmid; and Marie Hardwick for NEX-cre mice from Klaus-Armin Nave’s laboratory. This work was supported by a grant from the NIH ( R35 GM124824 to Z.Q.); AHA fellowships 19POST34410020 (J.Chen) and 18PRE34060025 (J.O.-O.); NIH fellowship F31 NS108658 (M.d.C.V.); and Johns Hopkins University School of Medicine . This paper is dedicated to the memory of our dear friend and wonderful colleague, Maria del Carmen Vitery, who recently passed away.
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/5/22
Y1 - 2019/5/22
N2 - 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. 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.
AB - 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. 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.
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U2 - 10.1016/j.neuron.2019.03.029
DO - 10.1016/j.neuron.2019.03.029
M3 - Article
C2 - 30982627
AN - SCOPUS:85065185003
SN - 0896-6273
VL - 102
SP - 813-827.e6
JO - Neuron
JF - Neuron
IS - 4
ER -