Neurons in the central auditory system respond to sound stimuli in ways that allow the brain to encode characteristics such as the frequency, intensity and localization of the stimuli. The way that a particular neuron responds depends to a large degree on the specific combination of ion channel proteins that are expressed in that neuron. The Kv3.1 and Kv1.3 genes encode voltage-dependent potassium channels that are found in many auditory neurons. The Kv3.1 channel is, in particular, found at very high levels at the synaptic junctions of neurons that are capable of locking their action potentials in phase with the frequency of auditory stimuli. The electrical characteristics of this channel suggest that its presence allows cells faithfully to follow the timing of high frequency synaptic inputs. We plan to test the role of the Kv3.1 and Kv1.3 channels directly by recording the responses of auditory neurons in which these channels have been deleted by knockout of the genes, or by antisense oligonucleotides that block transcription of the genes. Ongoing work suggests that there exists a gradient of expression of Kv3.1 protein in some auditory nuclei and that the expression of Kv3.1 channels may be regulated by neuronal activity. To determine the factors that control the level of the Kv3.1 channel and other potassium channels in auditory neurons, we shall measure the levels of potassium current, and the levels of channel mRNA and protein following depolarization of the cells or after treatment with neurotransmitter and growth factors that are known to influence the activity of auditory neurons. We shall also generate transgenic mice in which different regions of the promoters of the Kv3.1 and Kv1.3 genes are linked to a reporter gene. By determining the response to the reporter gene to stimulation of intact neurons, we shall determine which elements in the promoter are required for the gene to be regulated in vivo. Understanding the molecular basis of how ion channels are expressed and regulated in different types of auditory neurons is likely to lead to an understanding of certain forms of deafness, as well as disorders in the interpretation of auditory stimuli and abnormal excitability such as audiogenic seizures.
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