Phasic/tonic glial GABA differentially transduce for olfactory adaptation and neuronal aging

Hankui Cheng; Du Chen; Xiao Li; Umar Al-Sheikh; Duo Duan; Yuedan Fan; Linhui Zhu; Wanxin Zeng; Zhitao Hu; Xiajing Tong; Guohua Zhao; Yongming Zhang; Wenjuan Zou; Shumin Duan; Lijun Kang

doi:10.1016/j.neuron.2024.02.006

Phasic/tonic glial GABA differentially transduce for olfactory adaptation and neuronal aging

Neuron. 2024 Mar 1:S0896-6273(24)00090-4. doi: 10.1016/j.neuron.2024.02.006. Online ahead of print.

Authors

Hankui Cheng¹, Du Chen¹, Xiao Li¹, Umar Al-Sheikh¹, Duo Duan¹, Yuedan Fan¹, Linhui Zhu¹, Wanxin Zeng², Zhitao Hu³, Xiajing Tong², Guohua Zhao⁴, Yongming Zhang⁵, Wenjuan Zou¹, Shumin Duan⁶, Lijun Kang⁷

Affiliations

¹ Department of Neurology of the Fourth Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Yiwu 322000, China; MOE Frontier Science Center for Brain Science and Brain machine Integration, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310053, China.
² School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
³ Department of Neuroscience, City University of Hong Kong, Kowloon, China.
⁴ Department of Neurology of the Fourth Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Yiwu 322000, China.
⁵ Department of Ophthalmology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, China.
⁶ MOE Frontier Science Center for Brain Science and Brain machine Integration, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310053, China.
⁷ Department of Neurology of the Fourth Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Yiwu 322000, China; MOE Frontier Science Center for Brain Science and Brain machine Integration, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310053, China. Electronic address: kanglijun@zju.edu.cn.

PMID: 38447577
DOI: 10.1016/j.neuron.2024.02.006

Abstract

Phasic (fast) and tonic (sustained) inhibition of γ-aminobutyric acid (GABA) are fundamental for regulating day-to-day activities, neuronal excitability, and plasticity. However, the mechanisms and physiological functions of glial GABA transductions remain poorly understood. Here, we report that the AMsh glia in Caenorhabditis elegans exhibit both phasic and tonic GABAergic signaling, which distinctively regulate olfactory adaptation and neuronal aging. Through genetic screening, we find that GABA permeates through bestrophin-9/-13/-14 anion channels from AMsh glia, which primarily activate the metabolic GABA_B receptor GBB-1 in the neighboring ASH sensory neurons. This tonic action of glial GABA regulates the age-associated changes of ASH neurons and olfactory responses via a conserved signaling pathway, inducing neuroprotection. In addition, the calcium-evoked, vesicular glial GABA release acts upon the ionotropic GABA_A receptor LGC-38 in ASH neurons to regulate olfactory adaptation. These findings underscore the fundamental significance of glial GABA in maintaining healthy aging and neuronal stability.

Keywords: GABA; GABAergic receptors; glia-neuronal interaction; neuronal aging; olfactory adaptation; phasic inhibition; tonic inhibition.