Modeling AMPA receptor trafficking dynamics during long-term potentiation

Abstract

Neurons are excitable cells with a highly complex morphology. Their dendritic arbors stretch across thousands of micrometers and house tiny protrusion-like structures called "Spine," where they receive signals from other neurons. This signal transfer relies on the binding of neurotransmitters released from the presynaptic neuron the receptors localized in the post-synaptic density in the spine head. One of the essential types of receptors is the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). They mediate fast-excitatory currents necessary for information transfer from one neuron to another. Given the extensive dendritic structure, localizing AMPARs and modulating their copy numbers at each spine pose a tremendous logistical challenge for the neuron to ensure its function. In this thesis, I aim to provide novel insight into how neurons solve this logistical challenge and how their copy numbers are regulated by synaptic plasticity. <br /> Modern microscopy techniques coupled with advanced labeling methods allow the investigation of molecular composition and visualization of individual molecules in neuronal compartments such as dendrites and spines. However, analyzing this data is a challenging task. <br /> In this thesis, I introduce a novel tool called SpyDen, which I built to efficiently and robustly analyze neuronal imaging data and extract biologically meaningful information from them (discussed in Chapter 2). I discuss the details of my algorithmic solutions to trace dendritic branches and analyze fluorescent puncta like those found in neuronal imaging data. I also provide evidence of thorough validation of the tool to test its efficiency and robustness. <br /> Next, using a combination of mathematical models and experimental data analysis, I investigate the key trafficking steps and their kinetics necessary to explain the experimentally observed distribution of AMPARs and the distinct response of AMPAR subtype to LTP induction (discussed in Chapters 3 and 4). My findings reveal that mRNAs encoding for the AMPAR pore-forming subunits are localized predominantly in the somata. On the other hand, mRNA encoding for one of the most abundant AMPAR auxiliary subunits, CNIH-2, is highly enriched in the dendrites, undergoes local translation, and its rate of synthesis increases following chemical LTP induction. Next, I show that CNIH-2 translation is essential for inserting GluA2-containing AMPAR but not GluA1-homomeric receptors into the neuronal plasma membrane. Furthermore, including this selective trafficking of the AMAPR subtype in my mathematical model, I could accurately recapitulate the distinct temporal profiles of two major AMAPR subtypes: the fast and transient kinetics of calcium-permeable (GluA1-homomeric) AMPAR and the slow and persistent response of GluA2-containing AMPARs to plasticity induction.