Project 1: This summer research project will use high resolution imaging test the hypothesis that decoding of Ca2+-flux frequency by CaM and CaMKII plays a major role in dynamic actin polymerization and dendritic spine morphology. Student will learn basic laboratory skills, primary cell culture, immunohistochemistry, confocal imaging and image analysis.

Project 2: This summer research project will use computational modeling of Ca2+/Calmodulin and CaMKII interactions in dendritic spines to test the hypothesis that decoding of Ca2+-flux frequency by CaM and CaMKII plays a major role in dynamic actin polymerization and dendritic spine morphology. Computational tools that will be used include ordinary and partial differential equations and machine learning techniques to rapid explore model parameter space.

Research Question Overview:
Neuronal synapses are tightly regulated intercellular junctions that rapidly convey information from an upstream pre-synaptic neuron to a downstream post-synaptic neuron. Dynamic strengthening or weakening of synaptic connective strength, known as synaptic plasticity, is a critical feature of neuronal function. The direction of synaptic plasticity (increased connective strength (LTP) versus decreased connective strength (LTD)) depends on the timing of action potentials (AP), which is translated into frequency signals of Ca2+ ion flux through NMDA
receptors (NMDAR) located on dendritic spines (100-500nm mushroom-like protrusions that form the post-synapse).

The timing and direction of synaptic plasticity is also exquisitely regulated by dynamic organization and spatial localization of synaptic adhesion molecules, signaling receptors, ion channels, and the intracellular cytoskeleton within spines. However, it not clear to how these electrical, biochemical, and mechanical cues are integrated to produce robust, repeatable, and highly dynamic synaptic plasticity that lasts over the lifetime of a neuron (decades). Our recent work has shown that competition for CaM-binding can influence the Ca2+ frequency-dependence of protein activation and downstream signaling. In particular, the highly expressed Ca2+/calmodulin-dependent kinase II (CaMKII) plays a key role in synaptic plasticity via two
important aspects of its function: (1) CaMKII is highly involved in Ca2+-dependent signal transduction via phosphorylation of a number of downstream proteins including ion channels, guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and transcription factors, and (2) CaMKII acts as a multivalent scaffold that binds multiple proteins simultaneously and localizes them to post-synaptic spines, including both filamentous and monomeric actin and may regulate actin polymerization in the spine.

Big Data/Machine Learning, Biological Characterization and Imaging, Biological Simulation and Technology, Biotechnology Data Insights, Cellular Biology

• No Major Restriction

Weldon School of Biomedical Engineering

Tamara Kinzer-Ursem