Synaptopodins Role in Synaptic Plasticity and Neuronal Circuitry

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The connections between neurons, called synapses, are designed to rapidly and efficiently relay signals from one neuron to another. Such connections need to be stable in order to preserve important information while at the same time have enough flexibility to accommodate new information. Adaptation of synaptic networks during development and in response to injury or learning occurs through a continuous process of synapse formation and elimination. At least two distinct mechanisms play a central role in these processes: one involves a selective stabilization of synapses through activity-dependent mechanisms and a second involves modifications of synapse turnover and dynamics to allow network rewiring. The molecular mechanisms underlying these different aspects of synaptic structural plasticity are still largely unknown. My team have been investigating the mechanisms involved in why certain synapses are stable while others are more plastic. In the central nervous system, the majority of excitatory synapses are contained within dendritic protrusions called dendritic spines that have different shapes and synaptic strengths. The spines permit separation of the site of synaptic transmission from the dendritic shaft, which allows synapse-specific inputs and signal processing. Beyond the obvious variation of spine shape, intracellular components are heterogeneously distributed and can influence how a spine will functionally respond to plasticity-inducing stimuli and remodel morphologically. Interestingly a subset of spines within  the brain contains a complex endoplasmic reticulum (ER)-based organelle called the spine apparatus (SA). The SA is usually localized in the spine neck or at the base of the spine head and consists of laminar ER stacks with intervening electron-dense plates, connected to the main ER network and colocalizes with synaptopodin, an actin-binding protein and a marker for the SA. This structure serves as a calcium store, and is important for NMDA-dependent synaptic plasticity and homeostatic scaling in of the dentate gyrus (mechanism unknown). The SA contains the protein synaptopodin. Together, the presence or absence of the SA and synaptopodin can thus profoundly affect how a spine will react to synaptic transmission. However, it is still unclear if synaptopodin is involved in scaling other synapses or other facets of synaptic plasticity, such as synapse rewiring and what the mechanism. In this Discovery Grant we will build on preliminary data and in house tools to determine how synaptopodin prevents homeostatic scaling and if it is involved on other forms of plasticity. This research program will clarify the rules that govern information storage and rewiring of neuronal circuitry. The proposal will allow 3 graduate students to learn advanced optical, electrophysiology and biochemical techniques, and an undergraduate to learn imaging, reconstruction and western blotting, thus providing an ideal setting for the training of HQP.