Browsing by Subject "Neuronal excitability"
Now showing 1 - 2 of 2
Results Per Page
Sort Options
Item Mechanisms of benzyl alcohol tolerance in Drosophila melanogaster(2009-12) Alhasan, Yazan Mahmoud; Atkinson, Nigel (Nigel S.); Zakon, Harold H.; Gonzales, Rueben A.; Singer, Michael C.; Bergeson, Susan E.Proper neuronal function requires the preservation of appropriate neural excitability. An adaptive increase in neural excitability after exposure to agents that depress neuronal signaling blunts the sedative drug effects upon subsequent drug exposure. This adaptive response to drug exposure leads to changes in drug induced behaviors such as tolerance, withdrawal and addiction. Here I use Drosophila melanogaster to study the cellular and neuronal components which mediate behavioral tolerance to the anesthetic benzyl alcohol. I demonstrate that rapid tolerance to benzyl alcohol is a pharmacodynamic mechanism independent of drug metabolism. Furthermore, tolerance is a cell autonomous response which occurs in the absence of neural signaling. Using genetic and pharmacological manipulations I find the synapse to play an important role in the development of tolerance. In addition, the neural circuits that regulate arousal and sleep also alter benzyl alcohol sensitivity. Beyond previously described transcriptional mechanisms I find a post-translational role of the Ca2+-activated K+-channel, slowpoke in the development of tolerance. Finally, I explore a form of juvenile onset tolerance, which may have origins that differ from rapid tolerance. The implications of this study go beyond tolerance in Drosophila melanogaster to benzyl alcohol and can shed light on human drug tolerance, withdrawal and addiction.Item Persistent and transient Na⁺ currents in hippocampal CA1 pyramidal neurons(2011-08) Park, Yul Young; Johnston, Daniel, 1947-; Bajaj, Chandrajit L.; Ben-Yakar, Adela; Dunn, Andrew; Shouval, HarelThe biophysical properties and distribution of voltage gated ion channels shape the spatio-temporal pattern of synaptic inputs and determine the input-output properties of the neuron. Of the various voltage-gated ion channels, persistent Na⁺ current (INaP) is of interest because of its activation near rest, slow inactivation kinetics, and consequent effects on excitability. Overshadowed by transient Na⁺ current (INaT) of large amplitude and fast inactivation, various quantitative characterizations of INaP have yet to provide a clear understanding of their role in neuronal excitability. We addressed this question using quantitative electrophysiology to compare somatic INaP and INaT in 4–7 week old Sprague-Dawley rat hippocampal CA1 pyramidal neurons. INaP was evoked with 0.4 mV/ms ramp voltage commands and INaT with step commands in hippocampal neurons from in vitro brain slices utilizing nucleated patch-clamp recording. INaP was found to have a density of 1.4 ± 0.7 pA/pF in the soma. Compared to INaT, it has a much smaller amplitude (2.38% of INaT) and distinct voltage dependence of activation (16.7 mV lower half maximal activation voltage and 41.3% smaller slope factor than those of INaT). The quantitative measurement of INaT gave the activation time constant ([tau]m) of 22.2 ± 2.3 [mu]s at 40 mV. Hexanol, which has anesthetic effects, was shown to preferentially block INaP compared to INaT with a significant voltage threshold elevation (4.6 ± 0.7 mV) and delayed 1st spike latency (221 ± 54.6 ms) suggesting reduced neuronal excitability. The number of spikes evoked by either given step current injections or [alpha]-EPSP integration was also significantly decreased. The differential blocking of INaP by halothane, a popularly used volatile anesthetic, further supports the critical role of INaP in setting voltage threshold. Taken together, the presence of INaP in the soma demonstrates an intrinsic mechanism utilized by hippocampal CA1 pyramidal neurons to regulate axonal spike initiation through different biophysical properties of the Na⁺ channel. Furthermore, INaP becomes an interesting target of intrinsic plasticity because of its profound effect on the input-output function of the neuron.