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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Talley, Edmund M
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Burette, Alain C; Park, Haram; Weinberg, Richard J (2014) Postsynaptic distribution of IRSp53 in spiny excitatory and inhibitory neurons. J Comp Neurol 522:2164-78
Racz, Bence; Weinberg, Richard J (2013) Microdomains in forebrain spines: an ultrastructural perspective. Mol Neurobiol 47:77-89
Burette, Alain C; Weinberg, Richard J; Sassani, Patrick et al. (2012) The sodium-driven chloride/bicarbonate exchanger in presynaptic terminals. J Comp Neurol 520:1481-92
Wang, Xiaoming; McCoy, Portia A; Rodriguiz, Ramona M et al. (2011) Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3. Hum Mol Genet 20:3093-108
Larsen, Rylan S; Corlew, Rebekah J; Henson, Maile A et al. (2011) NR3A-containing NMDARs promote neurotransmitter release and spike timing-dependent plasticity. Nat Neurosci 14:338-44
Burette, A C; Strehler, E E; Weinberg, R J (2010) A plasma membrane Ca2+ ATPase isoform at the postsynaptic density. Neuroscience 169:987-93
Kenyon, Katharine A; Bushong, Eric A; Mauer, Amy S et al. (2010) Cellular and subcellular localization of the neuron-specific plasma membrane calcium ATPase PMCA1a in the rat brain. J Comp Neurol 518:3169-83
Jacob, Amanda L; Jordan, Bryen A; Weinberg, Richard J (2010) Organization of amyloid-beta protein precursor intracellular domain-associated protein-1 in the rat brain. J Comp Neurol 518:3221-36
Hung, Albert Y; Futai, Kensuke; Sala, Carlo et al. (2008) Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1. J Neurosci 28:1697-708
Welch, Jeffrey M; Lu, Jing; Rodriguiz, Ramona M et al. (2007) Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature 448:894-900

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