Phasic/Tonic Glial GABA Differentially Transduce for Olfactory Adaptation and Neuronal Aging

Neurology Medicine Basic Medical Sciences Biochemistry Life Sciences
olfactory adaptation neuronal aging glial cells GABA neuroprotection

Title Page

Background

Gamma-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain, regulating neuronal activity and plasticity through two distinct modes: phasic and tonic. However, our understanding of the mechanisms and physiological functions of GABA transmission in glial cells remains limited. Glial cells, especially astrocytes, can regulate synaptic homeostasis and behavior modulation by releasing gliotransmitters including GABA, glutamate, D-serine, and ATP. Despite studies showing that glial cells can synthesize and release GABA to maintain excitatory-inhibitory balance, the specific mechanisms remain incomplete.

To explore this issue further, we chose the model organism Caenorhabditis elegans, whose nervous system consists of only 302 neurons and 56 glial cells, similar in origin, development, morphology, and function to mammalian glial cells. This study focuses on the AMSH (Amphid Sheath) glial cells and their regulation of ASH (Amphid Single Cilium) neurons, investigating the effects of glial GABA transmission on olfactory adaptation and neuronal aging.

Source of the Paper

This article was completed by Hankui Cheng, Du Chen, Xiao Li, and other collaborators from the Institute of Brain Science and Brain Medicine, Zhejiang University School of Medicine, and was published in the May 1, 2024 issue of Neuron (Vol. 112, pp. 1473-1486). The primary corresponding author is Lijun Kang, reachable at kanglijun@zju.edu.cn.

Detailed Research Process

Experimental Process

In this study, the authors used a series of meticulous experiments to reveal the role of AMSH glial cell GABA signaling in ASH neurons:

  1. Genetic Screening and Mutant Construction:

    • Genetic screening showed that GABA diffuses through the Bestrophin-9/-13/-14 anion channels in AMSH glial cells, mainly activating the metabolic GABAB receptor (GBB-1) in the adjacent ASH neurons.
    • A series of deletion mutants and RNAi strains lacking GABA synthesis genes (such as unc-25) were created and validated to elucidate the role of GABA in glial-neuronal transmission.

  2. Calcium Imaging:

    • Calcium imaging technology was used to record the calcium responses of ASH neurons to assess excitability changes during aging.

  3. Behavioral Testing:

    • Olfactory avoidance behavior induced by 1-octanol was used to evaluate the olfactory adaptation ability of aging worms at different stages. Behavioral and physiological responses to 1-octanol and isoamyl alcohol (IAA) were observed to change significantly under different conditions.

  4. Morphological Analysis:

    • Microscope observations of bead-like structures formed in the dendrites of ASH neurons were conducted to evaluate aging-related morphological changes. These bead-like structures increased significantly with age, especially those containing dark vacuoles devoid of green fluorescent protein (GFP), suggesting a possible link to apoptosis.

  5. Specific Gene Restoration Experiments:

    • By restoring related genes (such as unc-25, bestrophins, etc.) in mutant AMSH glial cells, the regulatory effect of these genes on ASH neurons was evaluated.

Main Results

  1. GABA Regulation of Aging:

    • Over-excitation of ASH neurons was observed in unc-25 mutants and bestrophin mutants. Restoring unc-25 or bestrophins relieved this over-excitation, indicating that GABA regulates ASH neuron excitability and aging.

  2. GABA Regulation of Olfactory Adaptation:

    • GABA released via calcium-triggered vesicular release (UNC-47/VGAT), rather than through bestrophin channels, played a key role in olfactory adaptation of ASH neurons.

  3. Differential Roles of Receptors:

    • The primary role of metabolic GABAB receptors (GBB-1) in ASH neurons was to regulate aging, while ionotropic GABAA receptors (LGC-38) were involved in olfactory adaptation.

  4. Effects on ASH Neuron Morphology:

    • During aging, the absence of GABA signaling led to a significant increase in bead-like structures in ASH neuron dendrites. This phenomenon could be reversed by restoring unc-25 expression in AMSH glial cells.

Conclusions

By elucidating the mechanism of GABA transmission between AMSH glial cells and ASH neurons, this study reveals the different roles of GABA in regulating short-term olfactory adaptation and long-term neuronal aging in C. elegans. This research not only provides a new perspective on the role of glial cells in neural functions but also identifies potential targets for promoting healthy aging and neural homeostasis.

Research Highlights

  1. Dual-Mode GABA Transmission:

    • The study is the first to reveal the dual modes (phasic and tonic) of GABA release from glial cells in regulating neuronal adaptation and aging.

  2. Mechanism of Glial-Neuron Interaction:

    • Through genetic screening and specific gene manipulations, the study further elucidates the pathways of GABA release from glial cells and the differential activation of adjacent neuronal receptors, providing new insights into the excitatory-inhibitory balance in neural networks.

  3. Neuroprotective Effects:

    • The study shows that tonic GABA release can protect ASH neurons from age-related over-excitation and degenerative changes by activating GABAB receptors, offering new ideas for neurodegenerative disease research.

  4. Potential Applications:

    • The study proposes that regulating glial-neuronal GABAergic transmission may serve as a lifelong strategy to promote healthy aging and maintain neural homeostasis, with significant applied scientific value.

This study highlights the complexity of glial-neuronal interactions and their critical role in maintaining the stability of the nervous system, representing a significant advance in the field of neuroscience.