Tonic GABAergic Inhibition Is Essential for Nerve Injury-Induced Afferent Remodeling in the Somatosensory Thalamus and Ectopic Sensations

Yasuyuki Nagumo; Yoshifumi Ueta; Hisako Nakayama; Hironobu Osaki; Yuichi Takeuchi; Naofumi Uesaka; Masanobu Kano; Mariko Miyata

doi:10.1016/j.celrep.2020.107797

Tonic GABAergic Inhibition Is Essential for Nerve Injury-Induced Afferent Remodeling in the Somatosensory Thalamus and Ectopic Sensations

Cell Rep. 2020 Jun 23;31(12):107797. doi: 10.1016/j.celrep.2020.107797.

Authors

Yasuyuki Nagumo¹, Yoshifumi Ueta², Hisako Nakayama², Hironobu Osaki², Yuichi Takeuchi², Naofumi Uesaka³, Masanobu Kano⁴, Mariko Miyata⁵

Affiliations

¹ Department of Physiology, Division of Neurophysiology, School of Medicine, Tokyo Women's Medical University, Tokyo 162-8666, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
² Department of Physiology, Division of Neurophysiology, School of Medicine, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
³ Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Department of Cognitive Neurobiology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
⁴ Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; International Research Center for Neurointelligence (WPI-IRCN), The University of Tokyo Institutes for Advanced Study (UTIAS), The University of Tokyo, Tokyo 113-0033, Japan.
⁵ Department of Physiology, Division of Neurophysiology, School of Medicine, Tokyo Women's Medical University, Tokyo 162-8666, Japan. Electronic address: mmiyata@twmu.ac.jp.

PMID: 32579924
DOI: 10.1016/j.celrep.2020.107797

Abstract

Peripheral nerve injury induces functional and structural remodeling of neural circuits along the somatosensory pathways, forming the basis for somatotopic reorganization and ectopic sensations, such as referred phantom pain. However, the mechanisms underlying that remodeling remain largely unknown. Whisker sensory nerve injury drives functional remodeling in the somatosensory thalamus: the number of afferent inputs to each thalamic neuron increases from one to many. Here, we report that extrasynaptic γ-aminobutyric acid-type A receptor (GABA_AR)-mediated tonic inhibition is necessary for that remodeling. Extrasynaptic GABA_AR currents were potentiated rapidly after nerve injury in advance of remodeling. Pharmacological activation of the thalamic extrasynaptic GABA_ARs in intact mice induced similar remodeling. Notably, conditional deletion of extrasynaptic GABA_ARs in the thalamus rescued both the injury-induced remodeling and the ectopic mechanical hypersensitivity. Together, our results reveal a molecular basis for injury-induced remodeling of neural circuits and may provide a new pharmacological target for referred phantom sensations after peripheral nerve injury.

Keywords: VPM; ectopic mechanical hypersensitivity; extrasynaptic GABA(A) receptors; peripheral nerve injury; remodeling of lemniscal fibers; tonic inhibition; ventral posterior medial nucleus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Afferent Pathways / physiopathology*
Animals
Female
Male
Mice, Inbred C57BL
Mice, Transgenic
Nerve Tissue / injuries*
Nerve Tissue / physiopathology*
Neural Inhibition / physiology*
Neurons / metabolism
Protein Subunits / metabolism
Receptors, GABA-A / metabolism
Sensation / physiology*
Synapses / metabolism
Thalamus / physiopathology*
Ventral Thalamic Nuclei / physiopathology
gamma-Aminobutyric Acid / metabolism*

Substances

Protein Subunits
Receptors, GABA-A
gamma-Aminobutyric Acid