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Molecular Mechanisms of Synapse Formation in Development and Disease
Synapses are specialized cell-cell junctions which connect individual neurons together and are the sites of transmission of information between neurons. While the molecular mechanisms which promote synapse formation have been a subject of intense investigation, little is known about the molecular mechanismsthat limit synapse formation so that synapses form at the right time and place and in the correct numbers. We hypothesize that this step in the refinement of synaptic formation is crucial for the fine-tuning of neuronal connectivity and that signaling networks which limit synapses during development are either defective or inappropriately activated in cognitive disorders.Accordingly, our laboratory studies the signaling pathways that regulate synapse formation during normal brain developmentto begin to understand how, when these pathways go awry, human cognitive disorders develop. Currently projects include studies of: 1) Ephexin5: Ephexin5 is a guanine nucleotide-exchange factor (GEF) thatactivates the small G-protein RhoA, a regulator of the actin cytoskeleton. Genetic loss- and gain-of-function studies indicate that Ephexin5 acts to restrict spine growth and synapse development in the developing brain. Upon induction of EphrinB/EphB ligand-receptor signaling, Ephexin5 is rapidly phosphorylated in an EphB-dependent manner and targeted for proteasome-dependent degradation. These findings suggest that Ephexin5 functions as a barrier to excitatory synapse development until its degradation is triggered by EphrinB binding to EphBs. Interestingly, the degradation of Ephexin5 is mediated by Ube3A, a ubiquitin ligase whose expression level is altered in the human cognitive disorder Angelman Syndrome (AS) and in some forms of autism. This suggests that aberrant EphB/Ephexin5 signaling during synaptic development may contribute to the abnormal cognitive function observed in AS and autism. Using Ephexin5 our laboratory will pursue an understanding of the molecular pathways that regulate restriction of excitatory synapse formation and their relevance to the pathophysiology of Angelman Syndrome byaddressing the following questions: 1) What are the molecular determinants critical for Ube3A-mediated control of Ephexin5 degradation? 2) What molecular and cellular events underlie Ephexin5-mediated excitatory synapse restriction important for basic wiring of the nervous system? 3) What additional substrates of Ube3A are important for synapse formation? 2) New regulators of synapse formation: The goal of this studywill be to identify additional components of the genetic program thatrestrict synapse numbers using previouslydeveloped immunocytochemistry-based assay for neuronal synaptic connections in vitro. Specific targets will becorroborated using electrophysiological andin vivomorphologicalmeasurements. We are particularly interested in genes whose products function to restrict synapse formation early in development and are suggested to be defective or inappropriately activated in cognitive disorders.
PKCε Inhibits Neuronal Dendritic Spine Development through Dual Phosphorylation of Ephexin5.
Schaffer TB, Smith JE, Cook EK, Phan T, Margolis SS.
Cell Rep. 2018 Nov 27;25(9):2470-2483.e8.
Activity-Dependent Degradation of the Nascentome by the Neuronal Membrane Proteasome.
Ramachandran KV, Fu JM, Schaffer TB, Na CH, Delannoy M, Margolis SS.
Mol Cell. 2018 Jul 5;71(1):169-177.e6.
Reducing expression of synapse-restricting protein Ephexin5 ameliorates Alzheimer's-like impairment in mice.
Sell GL, Schaffer TB, Margolis SS.
J Clin Invest. 2017 May 1;127(5):1646-1650.
A mammalian nervous-system-specific plasma membrane proteasome complex that modulates neuronal function.
Ramachandran KV, Margolis SS.
Nat Struct Mol Biol. 2017 Apr;24(4):419-430.
A dual role for the RhoGEF Ephexin5 in regulation of dendritic spine outgrowth.
Hamilton AM, Lambert JT, Parajuli LK, Vivas O, Park DK, Stein IS, Jahncke JN, Greenberg ME, Margolis SS, Zito K.
Mol Cell Neurosci. 2017 Apr;80:66-74.
From UBE3A to Angelman syndrome: a substrate perspective.
Sell GL, Margolis SS.
Front Neurosci. 2015 Sep 15;9:322.
Margolis SS, Sell GL, Zbinden MA, Bird LM.
Neurotherapeutics. 2015 Jul;12(3):641-50.
EphB-mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation.
Margolis SS, Salogiannis J, Lipton DM, Mandel-Brehm C, Wills ZP, Mardinly AR, Hu L, Greer PL, Bikoff JB, Ho HY, Soskis MJ, Sahin M, Greenberg ME.
Cell. 2010 Oct 29;143(3):442-55.