Learning is crucial for survival. Learning involves the remodeling of synaptic connections in the brain which alters the strength of the synapses in response to activity. These changes in synaptic strength are known as synaptic plasticity. Synaptic plasticity has been a heavily studied topic since the discovery of long-term potentiation (LTP) by Bliss and Lomo in 1973. Much of this research focuses on the synaptic plasticity of connections in the hippocampus, a brain region which is critical for learning. It has been observed that learning can be more effective when using the spaced learning technique, where learning sessions are broken up by short breaks. Interestingly, it has been shown that spaced learning paradigms improve learning in animal models of Down’s and fragile X, which exhibit impaired learning. It has been proposed that this efficacy of spaced learning is due to saturation of plasticity, a state in which synapses become unresponsive to plasticity stimuli following the initial induction of plasticity. Saturation of plasticity has been observed in the hippocampus and artificial induction of saturation leads to learning deficits in rodents. It has also been shown that following the induction of plasticity at hippocampal circuits, these become unresponsive to further plasticity-inducing stimulation. After some time, these circuits can undergo plasticity again. Yet, how saturation of plasticity is occurring and what molecular mechanisms are responsible for the onset and offset of saturation have not been identified. I hypothesized that saturation of plasticity can occur at individual dendritic spines—membranous protrusions on dendrites which are the postsynaptic site of excitatory neurotransmission in the cortex. In Chapter 1 of this dissertation, I review the current literature on the molecular makeup of dendritic spines, their plasticity mechanisms and saturation of plasticity. Chapter 2 of this work contains experiments which I conducted to elucidate mechanisms which are involved in saturation of plasticity at individual spines. I show that plasticity can be saturated at individual dendritic spines and that after a period of 60 minutes, these same spines are able to undergo further plasticity. This time period of saturation can be described as a refractory period for plasticity. I also show that CaMKII signaling is impaired in saturated spines and that increasing the strength of the plasticity-inducing stimulation is not sufficient to recover their plasticity during the refractory period. Additionally, I show that the refractory period can be shortened by the overexpression of the synaptic scaffolding protein, PSD95. In Chapter 3, I explore mechanisms that may be related to saturation of plasticity, including a potential role for an NMDA receptor subunit switch, metabotropic glutamate receptor and the timing of the arrival of PSD95 at potentiated synapses. Chapter 4 of this work is a reflection of my contributions to the field of plasticity and my thoughts on the future directions on this line of research. Finally, I have included an Appendix in which I tested the role of mGluR5 in mGluR-mediated long-term depression (LTD) in spines of different sizes.

This report recognizes the variety of urban character and scale extant in downtown San Francisco as an important frame of reference for the way in which the city is seen and experienced both culturally and historically. The report provides a state-of-the-art analysis of sun access criteria for downtown streets and public open space and develops recommendations designed to protect and maintain the city's unique character.

This report describes a study by the U.C. Berkeley Environmental Simulation and Building Technology Laboratories of development in downtown San Francisco and its consequences for street level sun, wind, and thermal comfort conditions. The study grew out of San Francisco residents' increasing concerns about the quality of the downtown environment,and is related to the measures now being considered to implement the San Francisco Downtown Plan.

This study continues the work presented in the Simulation Laboratory's 1983 report, Sun and Light for Downtown San Francisco. That research concerned itself with the shadowing produced by downtown buildings, and recommended procedures and standards for preserving sunlight on downtown sidewalks and open spaces. This research takes the next steps, considering the effects of buildings on both sun and wind conditions at street level and evaluating the combined effects of these conditions on pedestrian comfort. Rather than considering just the effects of individual buildings, it evaluated the cumulative effects of area-wide development.

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