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; Maša Švent; Nadia Pilati; Charles Large; Nick Hartell; Martine Hamann

doi:10.3389/fncel.2021.721371

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

Front Cell Neurosci. 2021 Sep 3:15:721371. doi: 10.3389/fncel.2021.721371. eCollection 2021.

Authors

Timothy OIsen^{1

2}, Alberto Capurro^{1

3}, Maša Švent¹, Nadia Pilati⁴, Charles Large⁵, Nick Hartell¹, Martine Hamann^{1

3}

Affiliations

¹ Department of Neuroscience, Psychology and Behaviour, College of Life Sciences, University of Leicester, Leicester, United Kingdom.
² Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, CA, United States.
³ Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
⁴ Autifony Srl, Padua, Italy.
⁵ Autifony Therapeutics Limited, Stevenage Bioscience Catalyst, Stevenage, United Kingdom.

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.

Keywords: Kv3 K+ currents; auditory brainstem; calcium imaging; excitability; noise; pre-synaptic; synaptic release; synchrony.