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Title: Comparison of tonotopic gradients of basolateral potassium currents in inner hair cells of gerbils, guinea-pigs and mice
Author: Mitchell, Suzanne
ISNI:       0000 0001 3412 5459
Awarding Body: University of Sussex
Current Institution: University of Sussex
Date of Award: 2008
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In this thesis the existence and possible importance of any gradients in the basolateral potassium (K+) currents of adult mammalian inner hair cells (mCs) were investigated. Gradients in three K currents, the linopirdine sensitive current IK,n, a fast activating current IK,f' and a delayed rectifying current IK,s, were compared in three animal species, together with voltage responses and exocytosis as a proxy to neurotransmitter release. In gerbil IRCs IK,n increased towards the basal, high-frequency region, whereas in guinea-pigs and mice no gradient was observed. The hypothesized IK,n channel subunit KCNQ4 was transiently or stably transfected into cell lines. The current recorded from the transient transfections suggested KCNQ4 is indeed a good candidate for IK,n. However as the current changed characteristics after multiple passages ofthe cells it was concluded that a secondary intracellular factor may be required for the current to activate over the very negative range at which IK,n is active in the hair cells. IK,s was shown to increase tonotopically toward the high-frequency IRCs in the gerbil. This expression opposes the' gradient of IK,s in the guinea-pig. The expression of IK,f in the gerbil also differed from the guinea-pig. To compare how the various tonotopic gradients influence the membrane potential, membrane voltage were recorded in response to current injection. Comparisons were also made between exocytosis in the apical and basal mcs. In both gerbil and guinea-pig no difference was apparent in the voltage dependence of capacitance or calcium current between apical and basal mcs. Having established the normal physiological properties, the same techniques were used to study mature IHCs of the mouse mutant Snell's waltzer that lacks myosin VI, leading to recessive deafuess and vestibular defects. The mcs ofthese mice were found to have no IK,f or IK,n and current injection induced spike-like responses, indicating a defect in maturation. In addition, exocytosis was greatly reduced in homozygous mutants, suggestive of an involvement ofmyosin VI in exocytosis. In conclusion, no clear generally applicable role has emerged from the data in this thesis for tonotopic gradients of basolateral K+ currents in mammalian inner hair cells. However the presence and direction of tonotopic gradients, different in different species, is intriguing and merits further investigation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available