Identification and Characterization of Novel Mechanisms of Functional and Structural Synapse Remodeling: Focus on Vav Guanine Nucleotide Exchange Factors and MEF2 Transcription Factors
type: CreativeWork
description: Proper development of synaptic connectivity is a dynamic process requiring formation, elimination, maintenance, and plasticity of synapses. During early postnatal development, excess synapses are formed in most neural circuits, which are subsequently pruned during adolescence in a sensory- and activity-dependent mechanism. The brain also exhibits experience-dependent synaptic modifications that may enhance or weaken functional synapse strength. Investigation of numerous neurodevelopmental and psychiatric disorders reveals dysfunctions in synapse formation and function; however, underlying molecular mechanisms remain poorly understood. In Part One of this study, I identify a novel role for Vav guanine nucleotide exchange factors (GEFs) in brain-derived neurotrophic factor (BDNF)-dependent synapse plasticity. BNDF and its receptor, TrkB, are well-established positive modulators of hippocampal long-term potentiation (LTP), and increasing evidence suggests that BDNF/TrkB facilitates LTP in part through the stimulation of Rho GTPases and subsequent F-actin remodeling and dendritic spine structural dynamics. I report that Vav-family GEFs are activated by BDNF/TrkB signaling, and are required for BDNF-induced Rac-GTP formation. Vav GEFs, which are enriched at hippocampal glutamatergic synapses, are necessary for rapid BDNF-induced dendritic spine growth and CA3-CA1 LTP. Furthermore, Vav2/3-deficient mice have impaired contextual fear conditioning, as well as reduced anxiety. Together, findings support a role for Vav-dependent F-actin dynamics in BDNF-stimulated dendritic spine head enlargement and LTP, and normal hippocampal-dependent learning and memory and anxiety in mice. Part Two of this study reports the identification of common MEF2 and FMRP mRNA targets that are required for MEF2-induced synapse elimination. The activity-dependent transcription factor myocyte enhancer factor 2 (MEF2) is a key negative regulator of excitatory synapse number, promoting synapse removal…
abstract: Proper development of synaptic connectivity is a dynamic process requiring formation, elimination, maintenance, and plasticity of synapses. During early postnatal development, excess synapses are formed in most neural circuits, which are subsequently pruned during adolescence in a sensory- and activity-dependent mechanism. The brain also exhibits experience-dependent synaptic modifications that may enhance or weaken functional synapse strength. Investigation of numerous neurodevelopmental and psychiatric disorders reveals dysfunctions in synapse formation and function; however, underlying molecular mechanisms remain poorly understood. In Part One of this study, I identify a novel role for Vav guanine nucleotide exchange factors (GEFs) in brain-derived neurotrophic factor (BDNF)-dependent synapse plasticity. BNDF and its receptor, TrkB, are well-established positive modulators of hippocampal long-term potentiation (LTP), and increasing evidence suggests that BDNF/TrkB facilitates LTP in part through the stimulation of Rho GTPases and subsequent F-actin remodeling and dendritic spine structural dynamics. I report that Vav-family GEFs are activated by BDNF/TrkB signaling, and are required for BDNF-induced Rac-GTP formation. Vav GEFs, which are enriched at hippocampal glutamatergic synapses, are necessary for rapid BDNF-induced dendritic spine growth and CA3-CA1 LTP. Furthermore, Vav2/3-deficient mice have impaired contextual fear conditioning, as well as reduced anxiety. Together, findings support a role for Vav-dependent F-actin dynamics in BDNF-stimulated dendritic spine head enlargement and LTP, and normal hippocampal-dependent learning and memory and anxiety in mice. Part Two of this study reports the identification of common MEF2 and FMRP mRNA targets that are required for MEF2-induced synapse elimination. The activity-dependent transcription factor myocyte enhancer factor 2 (MEF2) is a key negative regulator of excitatory synapse number, promoting synapse removal…
author: Hale, Carly Fenwick
language: en
keywords: Cadherins, Fragile X Mental Retardation Protein, MEF2 Transcription Factors, Neuronal Plasticity, Proto-Oncogene Proteins c-vav, Synapses
date published: 2016-09-01T19:27:10Z
date modified: 2026-07-24T05:52:06Z
provider: University of Texas Southwestern Medical Center
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Texas Southwestern Medical Center

PropertyValue
property ID: Handle
value: https://hdl.handle.net/2152.5/3588