Saturation of Synaptic Plasticity at Individual Dendritic Spines

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Abstract The ability of organisms to learn is crucial for them to survive and adapt to new environments. Learning relies on the brain’s capacity to change the connections between neurons to alter circuit functions, or synaptic plasticity. Dysfunction in the regulation of synaptic plasticity, or ability of the brain to change in response to stimuli, has been implicated in neurological disorders like Alzheimer’s disease, autism spectrum disorder and drug addiction. Much of the research on the synaptic plasticity associated with learning has focused on dendritic spines, membranous protrusions that are the postsynaptic sites of excitatory transmission in the cortex. Notably, learning in humans is improved when breaks are incorporated into learning sessions, in a process called spaced learning. Notably, spaced training increases learning in rodent models of Fragile X, Angelman’s and Down syndromes, which are learning impaired. One idea is that the need for breaks is due to a temporary saturation of plasticity at the synapses involved in this learning. Indeed, it has been shown that saturation of potentiation leads to impairment of learning in animal models. After an initial stimulation leads to circuit potentiation, a second stimulus is unable to produce potentiation unless the intervals between stimuli were increased. However, the mechanisms that lead to saturation of plasticity remain poorly defined. The goal of this proposal is to determine the cellular and molecular mechanisms by which this saturation occurs. My current data show that saturation of synaptic strengthening occurs at individual synapse level and that the saturation occurs via postsynaptic mechanisms. My data also demonstrate that saturation of synaptic strengthening at individual spines can be overcome by increased levels of stimulation and that saturation is also release over time as spines stimulated 60 minutes after their initial stimulation are able to exhibit further synaptic strengthening. Finally, my data show that CaMKII activity is reduced in spines which are experiencing saturation. Using 2-photon (2p) imaging, 2p glutamate uncaging, calcium imaging and conditional single cell knock out animals, I propose to rigorously investigate the molecular and cellular mechanisms that drive saturation of plasticity at individual spines. The results of these experiments will further our knowledge of synaptic plasticity and its limitations and could elucidate novel drug targets for the treatment of neurological disorders and learning disabilities. After completing my dissertation, I intend to pursue a postdoctoral position studying the role of mitochondrial signaling and dysfunction in neurodegenerative diseases. The proposed experiments and training plan will provide a strong foundation for my transition to postdoctoral training and will support me in my long-term goal of an academic research position.