Long-term modifications in synaptic efficacy are implicated in learning and memory;dysfunction of this plasticity is implicated in a variety of neurodevelopmental and neuropsychiatric disorders. The long-term goal of this project is to elucidate the supramolecular organization of the postsynaptic density (PSD), which plays a central role in synaptic signal processing. This information may ultimately prove very useful in designing novel approaches to the prevention or treatment of brain disorders. The proposal for this funding cycle includes three specific aims:
Aim 1 is to develop new electron microscopic tools to study the ultrastructure of synapses, and to use these tools to study abnormalities of the PSD in mouse models of autism and schizophrenia.
Aim 2 is to examine how actin filaments attach to the PSD, to study the organization of two isoforms of a protein that links actin to the PSD, and to study two PSD-associated enzymes that control Rho-family proteins (molecular switches that modulate actin remodeling).
Aim 3 is to study the alignment of presynaptic release sites with postsynaptic receptors, and to explore possible disruptions in synaptic structure and receptor expression in mice that have mutations in synaptic adhesion molecules.

Public Health Relevance

Developmental disability, autism, and severe psychiatric disease represent a substantial drain on our country's resources, and a terrible human cost. By examining the structure of synapses in rodent brain, this research may provide a better understanding of the biological basis of these disorders, potentially leading to new approaches to prevention or treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039444-12
Application #
8689179
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Talley, Edmund M
Project Start
1999-10-01
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Burette, Alain C; Judson, Matthew C; Li, Alissa N et al. (2018) Subcellular organization of UBE3A in human cerebral cortex. Mol Autism 9:54
Simhal, Anish K; Gong, Belvin; Trimmer, James S et al. (2018) A Computational Synaptic Antibody Characterization Tool for Array Tomography. Front Neuroanat 12:51
Burette, Alain C; Judson, Matthew C; Burette, Susan et al. (2017) Subcellular organization of UBE3A in neurons. J Comp Neurol 525:233-251
Pappas, Andrea L; Bey, Alexandra L; Wang, Xiaoming et al. (2017) Deficiency of Shank2 causes mania-like behavior that responds to mood stabilizers. JCI Insight 2:
Judson, Matthew C; Burette, Alain C; Thaxton, Courtney L et al. (2017) Decreased Axon Caliber Underlies Loss of Fiber Tract Integrity, Disproportional Reductions in White Matter Volume, and Microcephaly in Angelman Syndrome Model Mice. J Neurosci 37:7347-7361
Xu, C Shan; Hayworth, Kenneth J; Lu, Zhiyuan et al. (2017) Enhanced FIB-SEM systems for large-volume 3D imaging. Elife 6:
Smith, Katharine R; Jones, Kelly A; Kopeikina, Katherine J et al. (2017) Cadherin-10 Maintains Excitatory/Inhibitory Ratio through Interactions with Synaptic Proteins. J Neurosci 37:11127-11139
Wu, Yumei; Whiteus, Christina; Xu, C Shan et al. (2017) Contacts between the endoplasmic reticulum and other membranes in neurons. Proc Natl Acad Sci U S A 114:E4859-E4867
Carstens, Kelly E; Phillips, Mary L; Pozzo-Miller, Lucas et al. (2016) Perineuronal Nets Suppress Plasticity of Excitatory Synapses on CA2 Pyramidal Neurons. J Neurosci 36:6312-20
Wang, Xiaoming; Bey, Alexandra L; Katz, Brittany M et al. (2016) Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism. Nat Commun 7:11459

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