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

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 (GABAAR)-mediated tonic inhibition is necessary for that remodeling. Extrasynaptic GABAAR currents were potentiated rapidly after nerve injury in advance of remodeling. Pharmacological activation of the thalamic extrasynaptic GABAARs in intact mice induced similar remodeling. Notably, conditional deletion of extrasynaptic GABAARs 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.

Highlights

Peripheral nerve injury frequently triggers referred phantom sensations that are perceived at a location other than the injured site
Potentiation of Extrasynaptic g-aminobutyric acid-type A receptor (GABAAR) Currents in the Ventral Posterior Medial Nucleus (VPM) of the Somatosensory Thalamus after Peripheral Nerve Injury Somatosensory information from the whiskers is transferred to the principal trigeminal nucleus (PrV) via the infraorbital nerve (ION), the second branch of the trigeminal nerve
We previously reported that an infraorbital nerve cut (IONC) in mice disrupts the normal, one-to-one connection of lemniscal fibers to VPM neurons, with recruitment of additional lemniscal fibers onto individual VPM neurons becoming apparent on approximately postoperative day 5 (POD5; Figure S1) (Takeuchi et al, 2012, 2017)

Summary

Introduction

Peripheral nerve injury frequently triggers referred phantom sensations that are perceived at a location other than the injured site. We found that complete transection of the whisker sensory nerve induces functional remodeling of afferent fibers in the somatosensory thalamus, such that the number of afferent inputs onto each thalamic neuron increases from one to many (Takeuchi et al, 2012). This remodeling is closely associated with somatotopic reorganization and ectopic mechanical hypersensitivity in the mandibular region (Takeuchi et al, 2017). Dynamic remodeling of CNS neuronal circuits by peripheral nerve injury has been intensively investigated, the underlying molecular mechanisms remain largely unknown

Methods

Results

Discussion

Conclusion