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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. [ABSTRACT FROM AUTHOR]

Exposure to loud sound (acoustic overexposure; AOE) induces hearing loss and damages cellular structures at multiple locations in the auditory pathway. Whether AOE can also induce changes in myelin sheaths of the auditory nerve (AN) is an important issue particularly because these changes can be responsible for impaired action potential propagation along the AN. Here we investigate the effects of AOE on morphological and electrophysiological features of the centrally directed part of the rat AN projecting from the cochlear spiral ganglion to brainstem cochlear nuclei. Using electron microscopy and immunocytochemistry, we show that AOE elongates the AN nodes of Ranvier and triggers notable perinodal morphological changes. Compound action potential recordings of the AN coupled to biophysical modeling demonstrated that these nodal and perinodal structural changes were associated with decreased conduction velocity and conduction block. Furthermore, AOE decreased the number of release sites in the cochlear nuclei associated with the reduced amplitudes of EPSCs evoked by AN stimulation. In conclusion, AN dysmyelination may be of fundamental importance in auditory impairment following exposure to loud sound. [ABSTRACT FROM AUTHOR]

Sound localization by auditory brainstem nuclei relies on the detection of microsecond interaural differences in action potentials that encode sound volume and timing. Neurons in these nuclei express high amounts of the Kv3.1 potassium channel, which allows them to fire at high frequencies with short-duration action potentials. Using computational modeling, we show that high amounts of Kv3.1 current decrease the timing accuracy of action potentials but enable neurons to follow high-frequency stimuli. The Kv3.1b channel is regulated by protein kinase C (PKC), which decreases current amplitude. Here we show that in a quiet environment, Kv3.1b is basally phosphorylated in rat brainstem neurons but is rapidly dephosphorylated in response to high-frequency auditory or synaptic stimulation. Dephosphorylation of the channel produced an increase in Kv3.1 current, facilitating high-frequency spiking. Our results indicate that the intrinsic electrical properties of auditory neurons are rapidly modified to adjust to the ambient acoustic environment. *Note: In the version of this article initially published online, some of the authors’ affiliations were incorrectly reported. These affiliations have been corrected for the HTML and print versions of the article. The correct affiliations are Ping Song 1 , Yue Yang 2 , Margaret Barnes-Davies 3,5 , Arin Bhattacharjee 1,5 , Martine Hamann 3 , Ian D Forsythe 4 , Douglas L Oliver 2 & Leonard K Kaczmarek 1 [ABSTRACT FROM AUTHOR]

The article studies the role performed by glutamate transporters in the homeostasis of glutamate in the brain. Glutamate transporters have a crucial function in controlling the extracellular concentration of glutamate in the brain. They remove glutamate from extracellular space and help terminate glutamatergic synaptic transmission. This prevents the extracellular concentration of glutamate from rising to neurotoxic levels.

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., Competing Interests: NP was employed by company Autifony Srl. CL was employed by company Autifony Therapeutics Limited. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 OIsen, Capurro, Švent, Pilati, Large, Hartell and Hamann.)

Exposure to loud sound increases burst-firing of dorsal cochlear nucleus (DCN) fusiform cells in the auditory brainstem, which has been suggested to be an electrophysiological correlate of tinnitus. The altered activity of DCN fusiform cells may be due to down-regulation of high voltage-activated (Kv3-like) K + currents. Whole cell current-clamp recordings were obtained from DCN fusiform cells in brain slices from P15-P18 CBA mice. We first studied whether acoustic over-exposure (performed at P15) or pharmacological inhibition of K + currents with tetraethylamonium (TEA) affect fusiform cell action potential characteristics, firing frequency and spike-timing relative to evoking current stimuli. We then tested whether AUT1, a modulator of Kv3 K + currents reverses the effects of sound exposure or TEA. Both loud sound exposure and TEA decreased the amplitude of action potential after-hyperpolarization, reduced the maximum firing frequency, and disrupted spike-timing. These treatments also increased post-synaptic voltage fluctuations at baseline. AUT1 applied in the presence of TEA or following acoustic over-exposure, did not affect the firing frequency, but enhanced action potential after-hyperpolarization, prevented the increased voltage fluctuations and restored spike-timing. Furthermore AUT1 prevented the occurrence of bursts. Our study shows that the effect on spike-timing is significantly correlated with the amplitude of the action potential after-hyperpolarization and the voltage fluctuations at baseline. In conclusion, modulation of putative Kv3 K + currents may restore regular spike-timing of DCN fusiform cell firing following noise exposure, and could provide a means to restore deficits in temporal encoding observed during noise-induced tinnitus., (Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.)