Dendritic spines are tiny appendages on the surface of many neurons that connect excitatory afferents with dendrites. They form separate biochemical micro-compartments and are considered sites of synaptic plasticity. Many spines of forebrain neurons contains a spine apparatus, an enigmatic organelle that consists of stacks of smooth endoplasmic reticulum intervened by actin filaments containing electron-dense plates. The precise function of the spine apparatus is unknown. Synaptopodin, which was identified and characterized by the investigator, is a proline-rich actin-binding protein of telencephalic dendrites and renal podocytes. The close association with the spine apparatus suggested that synaptopodin is an important component of this organelle. Here we will explore at the molecular level how synaptopodin is mechanistically involved in the biogenesis and dynamics of the spine apparatus. Based on our Preliminary Data we hypothesize that synaptopodin is required for the formation or maintenance of the spine apparatus. Synaptopodin may affect spine apparatus morphology by bundling actin filaments in the spine neck. To test this hypothesis, we propose the following two Specific Aims: the first Specific Aim will explore the role of synaptopodin in the formation and plasticity of the spine apparatus in mice. In the second Specific Aim we will elucidate the cellular mechanism by which synaptopodin contributes to the formation and plasticity of the spine apparatus The combination of biochemical, cellular, and molecular genetic approaches proposed in this application will provide insight into the biogenesis of spine apparatus formation and its regulation by synaptopodin. If our hypotheses are correct the work proposed here will have broad significance because it will a) define a molecule link between synaptopodin function and the biogenesis and plasticity of the spine apparatus and b) establish insight into the role of the spine apparatus in synaptic plasticity. This should in the long-term enable us to develop novel therapies that tackle learning deficiencies and memory loss by modulating the expression of synaptopodin thereby promoting the cellular plasticity of the dendritic spine apparatus.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA018886-04
Application #
7215276
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Pollock, Jonathan D
Project Start
2004-05-01
Project End
2009-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
4
Fiscal Year
2007
Total Cost
$345,138
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Zhang, Xiao-lei; Pöschel, Beatrice; Faul, Christian et al. (2013) Essential role for synaptopodin in dendritic spine plasticity of the developing hippocampus. J Neurosci 33:12510-8
Faul, Christian; Donnelly, Mary; Merscher-Gomez, Sandra et al. (2008) The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med 14:931-8
Faul, Christian; Asanuma, Katsuhiko; Yanagida-Asanuma, Etsuko et al. (2007) Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton. Trends Cell Biol 17:428-37
Reiser, Jochen; Mundel, Peter (2007) Dual effects of RAS blockade on blood pressure and podocyte function. Curr Hypertens Rep 9:403-8
Faul, Christian; Dhume, Ashwini; Schecter, Alison D et al. (2007) Protein kinase A, Ca2+/calmodulin-dependent kinase II, and calcineurin regulate the intracellular trafficking of myopodin between the Z-disc and the nucleus of cardiac myocytes. Mol Cell Biol 27:8215-27
Yanagida-Asanuma, Etsuko; Asanuma, Katsuhiko; Kim, Kwanghee et al. (2007) Synaptopodin protects against proteinuria by disrupting Cdc42:IRSp53:Mena signaling complexes in kidney podocytes. Am J Pathol 171:415-27
Asanuma, Katsuhiko; Yanagida-Asanuma, Etsuko; Faul, Christian et al. (2006) Synaptopodin orchestrates actin organization and cell motility via regulation of RhoA signalling. Nat Cell Biol 8:485-91
Asanuma, Katsuhiko; Kim, Kwanghee; Oh, Jun et al. (2005) Synaptopodin regulates the actin-bundling activity of alpha-actinin in an isoform-specific manner. J Clin Invest 115:1188-98
Faul, Christian; Huttelmaier, Stefan; Oh, Jun et al. (2005) Promotion of importin alpha-mediated nuclear import by the phosphorylation-dependent binding of cargo protein to 14-3-3. J Cell Biol 169:415-24