Throughout development and into adulthood, the mammalian nervous system exhibits an amazing capacity to change in response to experience. The basis for this functional plasticity rests with the ability of individual neurons to modify their connections in response to changing patterns of activity. In the mammalian cortex, the majority of excitatory synapses onto principal neurons occur on tiny actin-rich protrusions from the dendritic shaft called dendritic spines. Dendritic spines are highly motile structures that can appear and disappear within minutes. This dynamicity is thought to impart neurons with the ability to rapidly change their connectivity by establishing new synaptic connections. Neural activity has long been recognized to influence the formation of new spines, but the precise role of activity in stabilizing newly formed dendritic spine synapses has been poorly defined. One possibility is that the same activity patterns that induce long-lasting changes in the efficacy of existing synapses may also regulate the stability of nascent spines. Indeed, long-term potentiation (LTP) has been associated with transient increases in spine and synapse density. However, it is unclear whether LTP induction paradigms simply stimulate new spine formation, or if these stimulation paradigms simultaneously increase the stability of newly formed spines. In Chapter 2, I describe experiments aimed to test the hypothesis that LTP-inducing stimuli can increase the stability of nascent spines. These experiments provide the first direct evidence that LTP-inducing stimuli can increase the stability of individual newly formed spines. Chapter 3 describes a collection of experiments designed to elucidate the molecular basis for the activity-dependent new spine stabilization. In the first section of Chapter 3, I describe experiments intended to investigate the role of PKA-, CaMKII- or MEK-signaling in activity-dependent stabilization of new spines. In the second section of Chapter 3, I describe experiments designed to characterize the enrichment of the PSD-MAGUK scaffolding molecules, PSD-95, PSD-93, SAP-102 and SAP-97, in new spines and then to assess the effect of activity on PSD-MAGUK trafficking to nascent spines. The experiments described in the third section of Chapter 3 aimed to characterize the role of SynDIG1 in structural plasticity at individual spines. In Chapter 4, I describe experiments aimed at characterizing the effect of two commercially available uncaging reagents, MNI-glutamate and RuBi-glutamate, on spontaneous activity in cultured hippocampal slices. Collectively, the results of the experiments I describe in this thesis provide novel insight into how synaptic activity guides the remodeling of neural networks, which may in the future lead to novel approaches in the treatment of synaptic dysfunction in disease states.
|Commitee:||Burns, Marie E., Hell, Johannes W., McAllister, Kimberley, Pugh, Ed|
|School:||University of California, Davis|
|School Location:||United States -- California|
|Source:||DAI-B 75/01(E), Dissertation Abstracts International|
|Keywords:||Dendritic spines, Long-term potentiation, Organotypic slice culture, Synapse formation|
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