Cara Motz
BME PhD Proposal Presentation

Date:2022-06-24
Time: 11:00 am - 1:00 pm
Location / Meeting Link: UAW 3115 McIntire Conference Room + Zoom: https://gatech.zoom.us/j/93454178419?pwd=RFhZaW95NGNGZHhjTkRaeWI4eFZ6QT09 Meeting ID: 934 5417 8419 Passcode: 500296

Committee Members:
Cheng Zhu, PhD Machelle Pardue, PhD Ross Ethier, PhD Levi Wood, PhD Stephen Traynelis, PhD Andres Garcia, PhD


Title: The mechanobiology of the glutamate delta 1 receptor as related to synaptogenesis and neurological disorders

Abstract:
The body is rich with mechanical cues, and the brain is without exception, distinctly showing softer stiffnesses than other tissues at approximately <1kPa. However, how these cues impact function, especially at the neuronal, molecular level has been largely unexplored. In addition, with the identification of mechanosensitive channels such as PIEZOs, the concept that mechanical inputs can affect downstream signaling pathways, i.e., mechanotransduction, has attracted greater attention. The ionotropic glutamate receptor family consists of four main classes of receptors: NMDARs, Kainate Receptors, AMPARs, and the most elusive to date, glutamate delta receptors (GluDs). Despite sequence homology with its sister receptors, the GluD receptors, especially glutamate delta 1 (GluD1), do not function in a classically ionotropic way. Instead, they form a link, bridging pre- and post-synaptic terminals of neurons by binding to Neurexin 1b (Nrxnb) through an intermediate protein, Cerebellin (Cbln). Nrxnb, Cbln, and GluD, have been shown to modulate synaptogenesis, and Nrxnb and GluD have been shown to be genetically linked to neurodevelopmental and neuropsychiatric disorders such as Schizophrenia, autism spectrum disorder, and bipolar disorder. Supported by recent work suggesting that GluD functions as a signal transduction device, this project aims to elucidate the underpinnings of neuronal network formation in development through the cross-synaptic cleft interaction among GluD1, Cbln2, and Nrxnb. Our hypothesis is that GluD1–Cbln2–Nrxnb binding and function in synaptogenesis is regulated by neuron-generated, cytoskeleton/motor-dependent forces at the synaptic cleft. We propose to combine innovative biophysical tools (i.e. Biomembrane Force Probe, DNA-based molecular tension probes, and micropillar array detectors) with conventional neurobiological techniques (i.e. immunohistochemical staining and functional assays like calcium dynamics/patch clamp) to test our hypothesis in two specific aims: 1) generate GluD1, Nrxn1β and Cbln2 protein/cell systems and characterize their forcedependent 2D binding and 2) evaluate cell-generated forces on the Nrxn1-Cbln2-GluD1 complex and their role in synaptogenesis. The data to be generated will help understand the mechanoregulative mechanisms and function of GluD1, focusing on its role in synaptogenesis, and will pave the way for future work with the thousands of other synaptic cell adhesion molecules found at the synaptic terminal. Furthermore, greater insight into GluD1’s mechanism from this novel mechanobiological perspective could provide a clearer link between the genetic mutations associated with this tripartite complex and the associated neurodevelopmental and neuropsychiatric disorders.