Molecular mechanisms of synaptic plasticity

Abstract

Thesis: Ph. D. in Biological Chemistry, Massachusetts Institute of Technology, Department of Chemistry, 2016.Cataloged from PDF version of thesis. Vita.Includes bibliographical references.Synaptic plasticity serves as a central molecular mechanism underlying learning and memory formation in the brain. An increase in intracellular calcium concentrations triggered by neuronal activity induces synaptic plasticity, and calmodulin is a key protein that detects the elevated calcium levels and propagates downstream signaling. Neurogranin is a neuron-specific protein that binds to calmodulin and regulates the availability of calmodulin in the postsynaptic compartments of excitatory neurons. Dysregulation of neurogranin has been reported to cause altered synaptic plasticity as well as impairment in hippocampus-dependent learning, and is also associated with the higher risk of developing neurodegenerative and psychiatric diseases. Therefore, it is critical to understand how neurogranin regulates the induction of synaptic plasticity in the brain at the molecular level. The focus of this thesis is to examine how the changes in neurogranin expression levels contribute to the induction of synaptic plasticity in the hippocampus with a spike-timing-dependent plasticity paradigm and to understand the underlying molecular mechanisms. Using lentivirus-mediated manipulations of neurogranin levels in hippocampal CAl neurons, we found that increasing neurogranin levels in CAI neurons prolongs the timing window for spike-timing-dependent long-term potentiation (LTP), whereas acute knockdown of neurogranin inhibits the expression of LTP via regulating PP2B activity. We have also found that neurogranin interferes with calcium-dependent inactivation of neuronal L-type calcium channels and allows a sustained influx of calcium during the membrane depolarization in hippocampal neurons. Our results indicate that dynamic changes in neurogranin levels play a crucial role in setting the threshold for inducing LTP in spike-timing-dependent plasticity in the hippocampus.by Hongik Hwang.Ph. D. in Biological Chemistr