In axons, the action potential (AP) waveform determines the timing and strength of neurotransmission. Although the AP is classically thought of as a stereotyped """"""""all or none"""""""" signal, recent studies have shown that the axonal AP waveform is more malleable then once thought. One explanation is that a non-uniform distribution of voltage-sensitive potassium (Kv) channels exists within different axonal compartments. The relative inaccessibility of axons to electrophysiology has hampered exploration of this topic. This is especially true with respect to the small axons of interneurons, in which the axonal AP waveform has not been directly observed. To study the AP in interneuron axons, I developed a 2-photon (2P) voltage imaging technique to accurately report fast voltage changes with high spatial and temporal resolution. The compact cerebellar stellate cell was chosen, as these interneurons provide the sole source of inhibition within the cerebellum and play a vital role in the temporal integration of cerebellar output. Preliminary results show APs are shaped at individual boutons by locally expressed Kv channels, allowing AP waveform changes to occur at one bouton without perturbing the AP at nearby boutons. In addition, activity-dependent broadening of the AP occurred at boutons but not in connecting axon shafts, suggesting that inactivating Kv channels expressed at boutons were responsible for this effect. This proposal will explore local AP control in more detail. The 1st aim will determine which Kv subtypes are locally expressed at boutons as well as how local control influences synaptic strength within axons, utilizing patch-clamp recordings and 2P voltage and Ca2+ imaging/uncaging Kv inhibitor. The 2nd aim will uncover which Kv subtypes allow for rapid activity-dependent broadening and the impact of this phenomenon on synaptic transmission. Results from these aims will present new data on how interneuron axons perform complex computations in a site-specific manner, leading to a more complete understanding of neuronal processing.

Public Health Relevance

The fundamental unit of communication in brain cells is the action potential, which is generated and shaped by specialized proteins called ion channels. Ion channel dysfunction has been implicated in many neurological disorders. This proposal will perform a novel and detailed exploration of potassium ion channels that control the action potential, thereby expanding our knowledge of brain function and pathology.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F03B-G (20))
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Silberberg, Shai D
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Max Planck Florida Corporation
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Rowan, Matthew J M; Bonnan, Audrey; Zhang, Ke et al. (2018) Graded Control of Climbing-Fiber-Mediated Plasticity and Learning by Inhibition in the Cerebellum. Neuron 99:999-1015.e6
Amat, Samantha B; Rowan, Matthew J M; Gaffield, Michael A et al. (2017) Using c-kit to genetically target cerebellar molecular layer interneurons in adult mice. PLoS One 12:e0179347
Rowan, Matthew J M; Christie, Jason M (2017) Rapid State-Dependent Alteration in Kv3 Channel Availability Drives Flexible Synaptic Signaling Dependent on Somatic Subthreshold Depolarization. Cell Rep 18:2018-2029
Rowan, Matthew J M; DelCanto, Gina; Yu, Jianqing J et al. (2016) Synapse-Level Determination of Action Potential Duration by K(+) Channel Clustering in Axons. Neuron 91:370-83
Rowan, Matthew J M; Tranquil, Elizabeth; Christie, Jason M (2014) Distinct Kv channel subtypes contribute to differences in spike signaling properties in the axon initial segment and presynaptic boutons of cerebellar interneurons. J Neurosci 34:6611-23