Thesis Committee: Ryohei Yasuda (Advisor), Stephen Teitsworth, Henry Greenside
Despite significant advances in neurobiology, the biochemical and physical principles underlying learning and memory are still poorly understood. It is widely believed that the key to explaining these phenomena lies in the nature of synapses, the junctions through which neurons communicate. Synapses are highly dynamic sites. In addition to the significant chemical and electrical activity occurring at each synapse, the brain is constantly creating new synapses while destroying, strengthening, or weakening existing ones. Numerous events occur during such processes, including the activation of gene expression and modification of proteins. Synaptic plasticity, the ability of neurons to alter the strength of their interactions with one another, is believed to be one of the primary cellular mechanisms underlying learning and memory. Several models of learning involve the encoding of memories in networks of neurons through changes in the weight of interaction between pairs of neurons.
The main sites of communication between many neurons are dendritic spines, small protrusions that receive chemical signals. Pathways controlling spine morphology have been implicated in many congenital disorders, including mental retardation . One of these pathways involves Cdc42, a signaling protein known to be involved in the morphogenesis of dendritic spines . The size and shape of a spine are likely related to the strength of its synapse and change rapidly in response to chemical signals from other neurons. In this project, we attempt to link the activity of Cdc42 to e?ects on synaptic plasticity by observing how changes in dendritic spine volume are influenced by the absence of Cdc42. Two-photon microscopy, a high resolution technique useful for imaging in biological tissues, is utilized to image dendritic spines in hippocampal slices from knockout mice that do not express Cdc42 as well as wild-type mice. We show here that, upon stimulation by glutamate molecules, neurons lacking Cdc42 exhibit significantly decreased sustained spine volume changes when compared to wild-type cells. These results suggest that Cdc42 plays a key role in maintaining long-term structural plasticity and, therefore, is crucial to the encoding of memories.
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