The significance of the low voltage-gated potassium channel subunit Kv1.1 for the processing of sound source location

Viac o knihe

Voltage-gated potassium (Kv) channels constitute an important element to regulate neuronal excitability by determining the dynamic of repolarization during the generation of action potentials (APs) and thereby influencing width, latency, and frequency of APs. The voltage-gated potassium channel subunit Kv1.1 got into the focus of neurobiological research because humans with mutations in the appropriate gene locus KCNA1 were affected by ataxia and exhibited an increased probability of getting epilepsy highlighting the significance of this single protein for the excitability of the nervous system. In the present thesis, the murine auditory system is used as a model system to examine the significance of Kv1.1 for the processing of sound source location which is known to depend on high temporal precision of AP generation and transmission. The encoding of azimuthal sound location in mice relies on the processing of interaural intensity differences (IIDs) first accomplished by neurons of the lateral superior olive (LSO) of the auditory brainstem through bilateral integration of excitatory and inhibitory inputs. This binaural information is then conveyed to the inferior colliculus (IC) of the midbrain. Electrophysiological single cell recordings in vivo revealed limited IID sensitivity of LSO neurons to IIDs corresponding to the ipsilateral sound field. Reduced efficiency of IID encoding and the lack of inhibitory effects at high inhibitory stimulus intensities could be reproduced by a computational model solely by the increment in temporal variability of the inhibitory input. Electrophysiological recordings in IC neurons revealed the importance of Kv1.1 for the maintenance of latency disparities. The behavioral performance in the detection of a change in sound location was impaired in Kcna1-/- mice. The paradigm of prepulse inhibition (PPI) of the acoustic startle response (ASR) was applied to evaluate the ability of Kcna1-/- and wild-type mice to discriminate different sound sources under binaural and monaural listening conditions. Wild-type mice were affected by the reduced availability of IIDs, whereas knockout mice could not benefit from binaural difference cues for the detection of a change in noise location. This study provided evidence for a general disturbance of binaural integration in Kcna1-/- mice and elucidates the contribution of voltage-gated potassium channels to the temporal adjustment of converging excitation and inhibition. This thesis therefore importantly contributes to the understanding of neuronal excitability and may help to expand the knowledge about disease patterns of human patients that are affected by a mutation of the KCNA1 gene locus.