Sparsely Distributed, Pre-synaptic Kv3 K+ Channels Control Spontaneous Firing and Cross-Unit Synchrony via the Regulation of Synaptic Noise in an Auditory Brainstem Circuit.

Timothy Oisen,Alberto Capurro,Charles Large,Martine Hamann,Nick Hartell,Maša Švent,Nadia Pilati

doi:10.3389/fncel.2021.721371

Abstract

Spontaneous subthreshold activity in the central nervous system is fundamental to information processing and transmission, as it amplifies and optimizes sub-threshold signals, thereby improving action potential initiation and maintaining reliable firing. This form of spontaneous activity, which is frequently considered noise, is particularly important at auditory synapses where acoustic information is encoded by rapid and temporally precise firing rates. In contrast, when present in excess, this form of noise becomes detrimental to acoustic information as it contributes to the generation and maintenance of auditory disorders such as tinnitus. The most prominent contribution to subthreshold noise is spontaneous synaptic transmission (synaptic noise). Although numerous studies have examined the role of synaptic noise on single cell excitability, little is known about its pre-synaptic modulation owing in part to the difficulties of combining noise modulation with monitoring synaptic release. Here we study synaptic noise in the auditory brainstem dorsal cochlear nucleus (DCN) of mice and show that pharmacological potentiation of Kv3 K+ currents reduces the level of synaptic bombardment onto DCN principal fusiform cells. Using a transgenic mouse line (SyG37) expressing SyGCaMP2-mCherry, a calcium sensor that targets pre-synaptic terminals, we show that positive Kv3 K+ current modulation decreases calcium influx in a fifth of pre-synaptic boutons. Furthermore, while maintaining rapid and precise spike timing, positive Kv3 K+ current modulation increases the synchronization of local circuit neurons by reducing spontaneous activity. In conclusion, our study identifies a unique pre-synaptic mechanism which reduces synaptic noise at auditory synapses and contributes to the coherent activation of neurons in a local auditory brainstem circuit. This form of modulation highlights a new therapeutic target, namely the pre-synaptic bouton, for ameliorating the effects of hearing disorders which are dependent on aberrant spontaneous activity within the central auditory system.

Highlights

We demonstrate that Kv3 K+ channels are sparsely localized to a proportion of pre-synaptic boutons in the dorsal cochlear nucleus (DCN), and that their increased activation reduces the level of synaptic noise and the spontaneous firing rates of DCN principal fusiform cells
We show the mechanisms by which a single type of ion channel (Kv3 K+ channels) localized to pre-synaptic boutons exert a powerful modulatory effect on synaptic noise and network-level excitability in an auditory brainstem circuit associated with the induction of tinnitus
Our study focused on the DCN because of hyperexcitability well characterized in that auditory structure (Kaltenbach, 2006; Wu et al, 2016)

Summary

Introduction

Biological noise is ubiquitous throughout sensory systems and enhances the detection of weak signals via stochastic resonancebased mechanisms (Longtin, 1993; Wiesenfeld and Moss, 1995; Collins et al, 1997; Simonotto et al, 1997; Jaramillo and Wiesenfeld, 1998; Moss et al, 2004; Krauss et al, 2018). When present in excess, noise can distort incoming sensory signals (Collins et al, 1997; Simonotto et al, 1997; Bidelman, 2017; Bidelman et al, 2020). Voltage-activated K+ channels (Kv) are known to have a major role in the regulation of networklevel excitability in the central auditory system (Song et al, 2005; Steinert et al, 2011; Pilati et al, 2012; Li et al, 2015), but the pre-synaptic contribution of Kv channels to excitability remains relatively unstudied

Methods

Results

Conclusion