Regulation Of Plasma Membrane Properties in Excitable Cells by Wnt Signaling

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Excitable cells produce, amplify, and propagate electrical signals. In the nervous system, these cells carry the information that allows multicellular organisms to coordinate a range of sensory and motor functions, from producing simple escape responses to orchestrating sophisticated learning and cognitive behaviors. This project investigates fundamental molecular and cellular properties of neurons regulated by Wnt signaling, a highly conserved cellular signaling pathway that regulates animal embryonic development but is also present in the mature central nervous system (where its function is still poorly understood). Preliminary data suggests that Wnt signaling in adults enables nerve cells to better synchronize their activity, a necessary step for proper information processing, memory formation, and cognition. Using a novel and systematic approach combining fluorescence imaging, electrophysiology, biochemistry, and molecular biology, this project will elucidate exactly how Wnt signaling regulates adult neuronal properties. This knowledge will further scientific understanding about how anatomically static neural circuits can adjust the responses of their cellular components to adaptively respond to changes in incoming stimuli. In addition, this project will offer training opportunities for students from underrepresented and disadvantaged communities in modern neuroscience techniques, and to participate in career development and networking events that will bolster their abilities to pursue careers in science and technology. The principal investigator will also carry out a number of activities that will contribute to generating a more diverse, equitable, and inclusive environment at the sponsoring institution, and in his own field of research. Wnt signaling is a highly conserved signal transduction pathway that regulates embryonic development of metazoans and is also present in the mature central nervous system of mammals, where its function is poorly understood. We have described a novel non-canonical Wnt signaling cascade that regulates trafficking of NMDA-type glutamate receptors (NMDARs) affecting synaptic plasticity, a cellular and molecular model of memory formation. Our most recent studies show that Wnt signaling in addition alters two key intrinsic properties of neurons: the resting membrane potential and the preferred resonant frequency that gives rise to coordinated oscillatory behaviors in cellular circuits. In a logical extension of our previous work, this project examines Wnt regulation of key plasma membrane ionic channels that shape cellular resonance and the metabolism of membrane lipids involved in such regulation. We hypothesize that Wnt signaling modulates intrinsic properties of cell membranes via modulation of the metabolism of plasma membrane lipids and key ion channels that underlie cellular resonance. We will: 1) identify the ion channels regulated by Wnt signaling that are involved in modulating intrinsic properties of neurons, and 2) establish whether Wnt signaling regulates distribution and availability of plasma membrane phospholipids that determine biophysical properties of membrane ion channel activities. The new information produced by this project is expected to lead to a greater understanding of how neural circuits adaptively regulate the properties of their constituent cells to help organisms cope with the constantly changing world around them.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.