EL PROCESO DE LA LITERATURA
XVI. MAGDA PORTAL
This dissertation focused on three specific aims to understand the physiological roles of NO and CO in neuronal development, specifically on how they affect growth cone motility. In aim 1, the electrical activity of developing neurons was shown to be a major determinant of growth cone calcium levels as well as the morphological response of a growth cone to NO. Fur- thermore, it was shown that the intrinsic characteristics of an AP, specifically its duration, can determine how guidance signals, like NO, affect growth cone motility. In aim 2, CO was identi- fied as an inhibitory signal, hyperpolarizing the membrane potential, silencing spontaneous firing activity, and decreasing neuronal excitability. Moreover, CO was shown to be an effector of mul- tiple ionic conductances to regulate this activity. Finally, in aim 3, CO was shown to increase fi- lopodial length through the activation of a sGC/PKG/RyR mediated pathway. Additionally, CO
treatment did not show any significant increases in calcium, but rather, it showed a decrease in growth cone calcium levels, which corresponded to the silencing of spontaneous firing activity. Collectively, these aims reveal novel mechanisms for the modulation of growth cone motility.
While NO and CO are both potent modulators of filopodial length, the primary mecha- nisms used by each gaseous signal for this modulation differs: NO effects are primarily mediated through electrical activity and CO effects are primarily mediated through a sGC pathway. More- over, the calcium dynamics regulated by these gases are different with NO increasing calcium and CO decreasing it. It is through these differences that NO and CO stand as separate unique modulators of growth cone motility, capable of differentially affecting growth cone responses to incoming guidance signals. These studies provide possible explanations for how specific growth cone behaviors can be generated and provide insight into how specific pathfinding trajectories can be generated in vivo. Overall, this dissertation provides a better understanding of the cellular mechanisms involved in the development and regeneration of the nervous system.
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