The Ca2+-activated chloride channel anoctamin-2 mediates spike-frequency adaptation and regulates sensory transmission in thalamocortical neurons.

Go Eun Ha,Kiyeong Song,Gyeong-Eon Chang,Eunji Cheong,Eun Mi Hwang,Hee-Sup Shin,Jea Kwon,C Justin Lee,Jaekwang Lee,Hankyul Kwak,Soon-Young Jung,Joohyeon Hong

doi:10.1038/ncomms13791

Abstract

Neuronal firing patterns, which are crucial for determining the nature of encoded information, have been widely studied; however, the molecular identity and cellular mechanisms of spike-frequency adaptation are still not fully understood. Here we show that spike-frequency adaptation in thalamocortical (TC) neurons is mediated by the Ca2+-activated Cl− channel (CACC) anoctamin-2 (ANO2). Knockdown of ANO2 in TC neurons results in significantly reduced spike-frequency adaptation along with increased tonic spiking. Moreover, thalamus-specific knockdown of ANO2 increases visceral pain responses. These results indicate that ANO2 contributes to reductions in spike generation in highly activated TC neurons and thereby restricts persistent information transmission.

Highlights

Neuronal firing patterns, which are crucial for determining the nature of encoded information, have been widely studied; the molecular identity and cellular mechanisms of spike-frequency adaptation are still not fully understood
Injection of a depolarizing 200 Perforated Whole cell (pA) current induced tonic firing with gradually increasing interspike intervals (ISIs) in artificial cerebrospinal fluid containing
The number of writhing responses were significantly greater in associated virus (AAV)-shANO2 mice than those in AAV-Scr mice (Fig. 8d), while there was no difference in the response between groups on the hot plate test (Supplementary Methods), which measures acute pain response (Supplementary Fig. 8 and Supplementary Note 8). These results suggest that knockdown of ANO2 in TC neurons increases pain responses via diminished spike adaptation in TC neurons in persistent types of pain, such as visceral pain; the effect may be less evident in acute pain

Summary

Introduction

Neuronal firing patterns, which are crucial for determining the nature of encoded information, have been widely studied; the molecular identity and cellular mechanisms of spike-frequency adaptation are still not fully understood. TC neurons generate tonic spikes at comparatively regular intervals at low frequency; they display patterns with gradual increases in interspike intervals (ISIs) when hyperactivated by depolarization[3] This form of activity-dependent spike-frequency adaptation is hypothesized as a mechanism for neuronal self-inhibition. Spike-frequency adaptation in neurons is associated with slowtype afterhyperpolarization (AHP) currents, which can be further categorized into medium AHP (mAHP) and very slow AHP currents (mIAHP and sIAHP), the decay kinetics of which are approximately hundreds of milliseconds and over seconds, respectively[21] Of these two types of currents, mAHP is known to be mediated by small conductance (SK) or large conductance (BK) Ca2 þ -activated K þ channels in many types of neurons, including hippocampal and cerebellar neurons[5,22,23]. The functionality of these channels in thalamic sensory information processing has not been studied

Methods

Results

Conclusion