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Abstract

The TWIK-related acid-sensitive potassium channel 5 (Task5) is a two-pore domain potassium channel (K2P) member. This potassium channel family forms leak channels, which are crucial for the setting of the resting membrane potential (RMP) and neuronal excitability. K2P channels are widely distributed throughout the body and are involved in a variety of biological functions such as ion homeostasis, neuroprotection and tumor progression. Shortly after its identification 19 years ago, Task5 was labeled as non-functional due to its lack of channel activity in heterologous expression systems. Among the K2P family members, Task5 has a very special expression pattern, as it is almost exclusively expressed within the auditory brainstem. In consideration of Task5’s restriction to auditory neurons, its upregulation during postnatal development and its deafness-associated downregulation, it appears quite probable that Task5 acts in developmental processes required for mature firing properties within the auditory brainstem circuitry and thus proper processing of auditory information. The present work investigated the physiological role of Task5 within two prominent auditory brainstem nuclei, the ventral cochlear nucleus (VCN) and the medial nucleus of the trapezoid body (MNTB). Special attention was laid on the functional relevance of Task5 in the regulation of neuronal excitability. To address this issue, the level of Task5 expression was manipulated either by its constitutive knockout or acute shRNA-mediated knockdown restricted to the VCN or the MNTB. Investigations were carried out mostly using various electrophysiological techniques. ShRNA-mediated knockdown showed a role for Task5 in contributing to the phasic firing pattern in VCN neurons, the RMP, cell excitability and regulation of the action potential (AP) waveform. Furthermore, we confirmed the developmental upregulation of Task5 around hearing onset in the VCN as well as in the MNTB. Interestingly and rather surprisingly, the results could not be replicated in constitutive Task5-knockout (KO) mice. Neurons in these mice were able to compensate for the loss of Task5 by adjusting their ion channel expression profile. However, Task5-KO mice showed alterations in auditory processing as shown by auditory brainstem recordings (ABRs). Furthermore, synaptic transmission at the endbulbs of Held, the output synapses of the auditory nerve (AN), was altered. Both results suggested independently of each other a perturbed signal propagation from the AN to the cochlear nucleus.These results suggest that Task5, despite its lack of channel activity in heterologous expression systems, performs an important function in physiological settings. Task5 contributes to the regulation of neuronal excitability, spike width, the establishment of the typical firing pattern of auditory neurons and the ultra-precise synaptic transmission. It can thus be concluded that Task5 plays an important role in the processing of auditory stimuli in the central auditory system.