Excitotoxicity leads to neuron death through a variety of mechanisms. Here, the focus is on calcium-mediated mechanisms of apoptosis that are triggered by excessive release of glutamate. Deafferentation of auditory neurons during a developmental critical period induces excitotoxicity within a subpopulation of cochlear nucleus neurons. In the first half of this dissertation, a specific mechanism for deafferentation-induced excitotoxicity of auditory neurons is described. Specifically, FAS death receptor mediated apoptosis is triggered by NFAT-dependent expression of the death receptor ligand FASL. The latter half of this dissertation includes a discussion of the neuroprotective effects of progesterone with regard to excitotoxicity triggered by brain injury. Calcium overload induced by an increase in extracellular glutamate is thought to be a major cause of injury-induced neuron death. There is overwhelming evidence that demonstrates the neuroprotective effects of progesterone against excitotoxicity in vitro and in models of traumatic brain injury or stroke injury. Although the use of progesterone as a means of therapy following traumatic brain injury has reached phase III clinical trials, the mechanism by which progesterone exerts its neuroprotective effects remains unknown. I sought to determine the mechanism underlying the neuroprotective effects of progesterone by analyzing the effect of progesterone on calcium signaling. I found that progesterone profoundly inhibits calcium influx through L-type calcium channels and as a consequence, progesterone blocks downstream effectors of calcium signaling. Interestingly, calcium flux through ionotropic glutamate receptors was unaffected by progesterone. These results suggest a progesterone-sensitive model of excitotoxicity-induced neuron death. In this mechanism, the trigger for excitotoxicity-induced apoptosis occurs by an initial activation of ionotropic glutamate receptors (progesterone insensitive), which leads to neuronal depolarization and secondary activation of L-type calcium channels (progesterone sensitive). The calcium flux through L-type calcium channels activates death-signaling cascades such as the mechanism characterized in the first half of the dissertation where NFAT activation leads to neuronal apoptosis.
University of Minnesota Ph.D. dissertation. December 2010. Major:Neuroscience. Advisor: Paul Gary Mermelstein, Ph.D. 1 computer file (PDF); viii, 103 pages. Ill. (some col.)
Luoma, Jessie Irene.
Molecular mechanisms of excitotoxicity: a mechanism for deafferentation-induced death and a mechanism underlying the neuroprotective effects of progesterone..
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