Synapses represent the basic unit of neuronal communications and are composed of paired pre- and post- synaptic terminals. Most of the excitatory synapses reside on dendritic spines, a type of dendritic protrusion that hosts neurotransmitter receptors and other postsynaptic specializations. Synapses are plastic and undergo short- and long-term modifications during developmental refinement of neuronal circuitry, as well as during learning and memory. Synaptic modifications involve both pre- and post-synaptic changes. At the postsynaptic site, directed trafficking of neurotransmitter receptors to and from the membrane surface is believed to be a key event underlying long-term potentiation (LTP) and depression (LTD), respectively. In addition, dendritic spines undergo rapid changes in their morphology during plasticity. The underlying cellular mechanisms that control and regulate these rapid changes in postsynaptic receptors and spine structures remain to be fully elucidated. The cytoskeleton controls many, if not all, aspects of the motility of celllar structures. How the cytoskeleton regulates postsynaptic structure, function, and modifications during plasticity, however, remains poorly understood. This proposed study aims to elucidate the actin mechanisms that control spine development, dynamics, and function. We will take advantage of our imaging expertise and experience in studying cytoskeletal dynamics in cultured neurons and organotypic slices to understand the actin regulation of postsynaptic structure and function. Specifically, we will test the novel hypothesis that coordinated monomeric G-actin localization and timely end capping of actin filaments are essential for spatiotemporal actin remodeling in the spine to underlie postsynaptic modifications during plasticity. Given that many neural disorders are associated with alterations in synaptic connections and plasticity, we hope to gain a better understanding of the molecular and cellular mechanisms underlying synaptic plasticity, which is of importance to our understanding of brain development and functions under both physiological and pathological conditions.

Public Health Relevance

Chemical synapses represent the major form of neuronal connections that undergo short- and long-term modifications during developmental refinement of neural circuits, as well as in learning and memory. The proposed study investigates the cytoskeletal regulation of postsynaptic structures and modifications associated with synaptic plasticity. This line of work is directly relevant to public health since it will contribute to our understanding of brain development and functions under both physiological and pathological conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH104632-02
Application #
8998069
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Asanuma, Chiiko
Project Start
2015-02-01
Project End
2020-01-31
Budget Start
2016-02-01
Budget End
2017-01-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Emory University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Omotade, Omotola F; Rui, Yanfang; Lei, Wenliang et al. (2018) Tropomodulin Isoform-Specific Regulation of Dendrite Development and Synapse Formation. J Neurosci 38:10271-10285
Lei, Wenliang; Myers, Kenneth R; Rui, Yanfang et al. (2017) Phosphoinositide-dependent enrichment of actin monomers in dendritic spines regulates synapse development and plasticity. J Cell Biol 216:2551-2564
Omotade, Omotola F; Pollitt, Stephanie L; Zheng, James Q (2017) Actin-based growth cone motility and guidance. Mol Cell Neurosci 84:4-10
Bienkowski, Rick S; Banerjee, Ayan; Rounds, J Christopher et al. (2017) The Conserved, Disease-Associated RNA Binding Protein dNab2 Interacts with the Fragile X Protein Ortholog in Drosophila Neurons. Cell Rep 20:1372-1384
York, Amanda L; Zheng, James Q (2017) Super-Resolution Microscopy Reveals a Nanoscale Organization of Acetylcholine Receptors for Trans-Synaptic Alignment at Neuromuscular Synapses. eNeuro 4:
Lei, Wenliang; Omotade, Omotola F; Myers, Kenneth R et al. (2016) Actin cytoskeleton in dendritic spine development and plasticity. Curr Opin Neurobiol 39:86-92
Myers, Kenneth R; Liu, Guanglu; Feng, Yue et al. (2016) Oligodendroglial defects during quakingviable cerebellar development. Dev Neurobiol 76:972-82
Rui, Yanfang; Zheng, James Q (2016) Amyloid ? oligomers elicit mitochondrial transport defects and fragmentation in a time-dependent and pathway-specific manner. Mol Brain 9:79
Li, Wenqi; Allen, Megan E; Rui, Yanfang et al. (2016) p39 Is Responsible for Increasing Cdk5 Activity during Postnatal Neuron Differentiation and Governs Neuronal Network Formation and Epileptic Responses. J Neurosci 36:11283-11294
Singh, Aditya K; McMillan, Jacob; Bukiya, Anna N et al. (2012) Multiple cholesterol recognition/interaction amino acid consensus (CRAC) motifs in cytosolic C tail of Slo1 subunit determine cholesterol sensitivity of Ca2+- and voltage-gated K+ (BK) channels. J Biol Chem 287:20509-21