Investigating the role of CELSRs, a family of adhesion-type GPCRs, in hippocampal neural circuit assembly

Vanderbilt University, Nashville TN

Investigators

Abstract

Summary Foundational to any actualized behavior are the processes of synapse formation and synaptic specificity that facilitates neural circuit wiring. These concerted efforts begin embryonically and are continuously refined throughout life. Therefore, any disruption in this system of actions can result in neurological disorders, which remain largely untreated due to the lack of knowledge of essential molecules and how they can respond to extracellular stimuli to promote intracellular bidirectional synaptic signaling. Adhesion class GPCRs have emerged as candidates for this role as they have been shown to be capable of extracellular adhesion and intracellular GPCR- mediated signal transduction. Latrophilin 2 and 3 are adhesion GPCRs that can mediate synapse formation as well as precise wiring of the hippocampus by activating a classical GPCR- signaling pathway. Interestingly, the only other adhesion GPCR, along with Latrophilin, to be conserved from vertebrates to invertebrates, is the Cadherin EGF Laminin-g Seven-pass G-type Receptor (CELSR) 1-3. Invertebrate models of CELSRs have been shown to mediate planar cell polarity, neuronal migration, dendritic growth, and axon guidance in the brain. However, CELSRs in this capacity have been critically understudied in the mammalian brain. Our lab has found that CELSRs are expressed in pyramidal cells of the hippocampus. CELSR2 and CELSR3 are the highest expressed and each possess unique cleavage properties. Consequently, my project strives to elucidate the role of CELSR2 and CELSR3 at mammalian hippocampal synapses by employing the use of novel epitope-tagged floxed conditional knockout mice. Aim #1 will characterize CELSR2 and CELSR3 function in knockout and control mice by employing electrophysiological assays and staining to assess synaptic neurotransmission and localization. Aim #2 will uncover the signaling mechanisms in which CELSR2 and CELSR3 mediate function via rescue electrophysiology experiments using previously found mutants of CELSR2 that prevent GαS coupling and CELSR3 seizure mutations located in the transmembrane region.