The reliability and precision of synaptic transmission are required by circuits of the auditory brainstem in order to encode timing with sub-millisecond accuracy. Synaptic transmission is refined by the complement of different ion channels at nerve terminals, which determines spike threshold and shape, and the ability to support high-frequency firing. The long-term goal of this research is to understand the synaptic mechanisms that contribute to these functions. Recently, an immunohistochemical study showed that an unusual K+ channel subtype, KCNQ5, is present at all excitatory terminals of the auditory brainstem. KCNQ (Kv7) channels are tightly associated with human neuronal and heart diseases. In the CNS, although the function of somatic KCNQ channels has been extensively examined in a variety of cell types, little attention has been paid to the synapse, in part because the small size of nerve terminals usually precludes their direct measurement. The calyx of Held, whose large size permits whole-cell patch-clamp recording, is an exceptional preparation that allows us direct analysis of presynaptic KCNQ channels. We found that the KCNQ5 channel is the major K+ channel responsible for setting the resting properties of the calyx. Modulation of the channel controls resting properties, subthreshold electrical activity, and transmitter release probability. Block of the channel also has profound effects on presynaptic excitability. In this application, we aim to determine how KCNQ channel controls the presynaptic excitability of auditory synapses. First, we will use a combination of immunohistochemistry, electrophysiology and 2-photon imaging to test the hypothesis that inhibition of KCNQ5 leads calyx of Held to altered spike firing as a result of inactivation of axonal and axon terminal ion channels (Kv1 and NaV). Results will be then incorporated into a complete model of propagation and excitation of presynaptic to account for the role of KCNQ. The modeling data will be confirmed by predicting the experimental results from partially blocking of key presynaptic channels. Since KCNQ5 is a component of all excitatory terminals in the lower auditory system, we will also examine the role of KCNQ at terminals in the cochlear nucleus whose function differs dramatically from the calyx. Preliminary data indicate that block of KCNQ channels suppresses exocytosis of granule cell parallel fiber into cartwheel cells, suggesting they may be required to maintain a full presynaptic spike waveform. We will examine the role of KCNQ in controlling transmitter release at terminals in the cochlear nucleus. The study of this proposal will extend our understanding of presynaptic KCNQ function, which may have implications for neurological disorders that are characterized by persistent activity, such as tinnitus or epilepsy. Thus, this application is important not only for basic science by enriching our knowledge of presynaptic ion channels and then physiological role KCNQ channel in the nervous system, but also for public health by providing possible insight into KCNQ-related diseases.
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NIH ExPorter