The proposed experiments will investigate the electrophysiological properties of myelinated axons and motor nerve terminals in frog, lizard and rat. We have developed intra-axonal recording techniques that permit the study of slow potential changes important in modulating axonal excitability. Our studies have already identified an unexpectedly slow component in the passive voltage response of these axons, and have demonstrated that action potentials are followed by a prolonged depolarizing afterpotential correlated with an increase in axonal excitability. Both these slow potentials can be accounted for by a revised electrical model that allows the large capacitance of the internodal axolemma to charge slowly during applied currents, and discharge slowly thereafter. We have used this revised electrical model to evaluate the effective resistances of the nodal and internodal axolemma and the myelin sheath, by analyzing the passive voltage response recorded in the axon. We also describe a modified voltage-clamp technique for measuring these resistances. These analytical techniques will be used to determine the mechanisms underlying changes in axonal passive properties and the depolarizing afterpotential produced by depolarization, potassium channel blocking agents, anti-myelin antibodies, and temperature changes, and to explore preliminary indications that repetitive axonal discharge leads to a transient reduction in the effective resistance of the myelin sheath. Other experiments will attempt to localize the major leakage pathways through or under the myelin sheath and to measure the frequency dependence on the axonal space constant. We will also attempt to localize and characterize slow ionic currents revealed by intra-axonal recordings. The proposed studies of myelin leakage pathways and slow ionic currents will expand our understanding of changes in axonal excitability following repetitive stimulation. The studies of physiological modulation of the myelin leakage resistance may suggest novel strategies for overcoming conduction block in demyelinating disorders.

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National Institute of Neurological Disorders and Stroke (NINDS)
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Neurology B Subcommittee 2 (NEUB)
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University of Miami School of Medicine
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White, Michael G; Saleh, Osama; Nonner, Doris et al. (2012) Mitochondrial dysfunction induced by heat stress in cultured rat CNS neurons. J Neurophysiol 108:2203-14
Nguyen, Khanh T; Barrett, John N; García-Chacón, Luis et al. (2011) Repetitive nerve stimulation transiently opens the mitochondrial permeability transition pore in motor nerve terminals of symptomatic mutant SOD1 mice. Neurobiol Dis 42:381-90
Nguyen, Khanh T; García-Chacón, Luis E; Barrett, John N et al. (2009) The Psi(m) depolarization that accompanies mitochondrial Ca2+ uptake is greater in mutant SOD1 than in wild-type mouse motor terminals. Proc Natl Acad Sci U S A 106:2007-11
Talbot, Janet D; Barrett, John N; Barrett, Ellen F et al. (2008) Rapid, stimulation-induced reduction of C12-resorufin in motor nerve terminals: linkage to mitochondrial metabolism. J Neurochem 105:807-19
White, Michael G; Luca, Luminita E; Nonner, Doris et al. (2007) Cellular mechanisms of neuronal damage from hyperthermia. Prog Brain Res 162:347-71
David, Gavriel; Nguyen, Khanh; Barrett, Ellen F (2007) Early vulnerability to ischemia/reperfusion injury in motor terminals innervating fast muscles of SOD1-G93A mice. Exp Neurol 204:411-20
Talbot, Janet; Barrett, John N; Barrett, Ellen F et al. (2007) Stimulation-induced changes in NADH fluorescence and mitochondrial membrane potential in lizard motor nerve terminals. J Physiol 579:783-98
Garcia-Chacon, Luis E; Nguyen, Khanh T; David, Gavriel et al. (2006) Extrusion of Ca2+ from mouse motor terminal mitochondria via a Na+-Ca2+ exchanger increases post-tetanic evoked release. J Physiol 574:663-75
Talbot, Janet D; David, Gavriel; Barrett, Ellen F (2003) Inhibition of mitochondrial Ca2+ uptake affects phasic release from motor terminals differently depending on external [Ca2+]. J Neurophysiol 90:491-502
David, Gavriel; Talbot, Janet; Barrett, Ellen F (2003) Quantitative estimate of mitochondrial [Ca2+] in stimulated motor nerve terminals. Cell Calcium 33:197-206

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