Integrin class adhesion receptors exert potent influences over trophic signaling and ion channels in various nonneuronal cells. Research in this program has shown that integrins are concentrated at synapses and influence neurotrophin expression, and glutamate receptor and ion channel properties in mature forebrain neurons. Specifically, the soluble integrin ligand peptide GRGDSP was found to up-regulate neurotrophin expression in an NMDA receptor (NMDAR)-dependent fashion. This led to the further discovery that GRGDSP treatment increases synaptic currents mediated by AMPA- and NMDA-class glutamate receptors and phosphorylation of the glutamate receptor themselves. The proposed work builds on these results and will test the hypothesis that synaptic integrins control local signaling cascades that regulate the functional properties of AMPA and NMDA receptors. There are 5 Specific Aims. In immunocytochemical studies of cultured hippocampal neurons, Aim 1 will identify integrin subunits and integrin signaling elements located in glutamatergic spine synapses. Studies will test if spines contain multiple integrins, if specific integrins and glutamate receptor proteins are co-distributed, and if the integrin signaling proteins FAK and Pyk2 are differentially distributed, in association with specific integrins, across glutamatergic spine synapses. In parallel studies to be conducted in acute hippocampal slices and synaptoneurosomes, Aim 2 will test the hypothesis that GRGDSP and native matrix ligands (fibronectin, vitronectin, laminin) activate synaptic integrin signaling leading to phosphorylation of AMPA and NMDA receptor proteins. Cotreatment with disintegrins and integrin neutralizing antisera will verify that effects are integrin-mediated and will identify the specific integrins involved.
Aim 3 will test the hypothesis that native integrin ligands potentiate NMDAR- and AMPAR-mediated synaptic responses in electrophysiological studies of acute hippocampal slices; integrin function blocking antibodies will be used to identify integrins mediating these effects and to test if integrin effects are tonic or only occur with new ligand presentation.
Aim 4 will test the hypothesis that treatment with integrin ligands alters specific AMPAR-scaffold associations and increases AMPAR surface expression in studies of acute hippocampal slices and cultured hippocampal neurons, respectively. Finally, Aim 5 will test the hypothesis that integrin signaling regulates neuronal gene expression through serial effects on NMDAR and VSCC function. Specifically, studies will test if integrin ligands trigger NMDAR-dependent phosphorylation of L-type VSCCs, will identify the specific integrins involved, and will use function blocking antibodies to test if integrin effects on neuronal gene expression are tonic or episodic (i.e., occur only with new ligand presentation). These studies will further characterize and identify novel interactions between adhesion and neurotransmitter receptors that influence both the potency of synaptic transmission and the regulation of neurotrophic factor expression in adult brain. As a consequence these findings are important for understanding basic mechanisms of neuronal communication and survival in the adult CNS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037799-08
Application #
7223513
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Mamounas, Laura
Project Start
1998-07-01
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2009-04-30
Support Year
8
Fiscal Year
2007
Total Cost
$300,944
Indirect Cost
Name
University of California Irvine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Chen, Yuncai; Rex, Christopher S; Rice, Courtney J et al. (2010) Correlated memory defects and hippocampal dendritic spine loss after acute stress involve corticotropin-releasing hormone signaling. Proc Natl Acad Sci U S A 107:13123-8
Rex, Christopher S; Chen, Lulu Y; Sharma, Anupam et al. (2009) Different Rho GTPase-dependent signaling pathways initiate sequential steps in the consolidation of long-term potentiation. J Cell Biol 186:85-97
Lin, C-Y; Hilgenberg, L G W; Smith, M A et al. (2008) Integrin regulation of cytoplasmic calcium in excitatory neurons depends upon glutamate receptors and release from intracellular stores. Mol Cell Neurosci 37:770-80
Lynch, Gary; Rex, Christopher S; Chen, Lulu Y et al. (2008) The substrates of memory: defects, treatments, and enhancement. Eur J Pharmacol 585:2-13
Lauterborn, Julie C; Rex, Christopher S; Kramar, Eniko et al. (2007) Brain-derived neurotrophic factor rescues synaptic plasticity in a mouse model of fragile X syndrome. J Neurosci 27:10685-94
Rex, Christopher S; Lin, Ching-Yi; Kramar, Eniko A et al. (2007) Brain-derived neurotrophic factor promotes long-term potentiation-related cytoskeletal changes in adult hippocampus. J Neurosci 27:3017-29
Chen, Lulu Y; Rex, Christopher S; Casale, Malcolm S et al. (2007) Changes in synaptic morphology accompany actin signaling during LTP. J Neurosci 27:5363-72
Lynch, Gary; Rex, Christopher S; Gall, Christine M (2006) Synaptic plasticity in early aging. Ageing Res Rev 5:255-80
Kramar, Eniko A; Lin, Bin; Rex, Christopher S et al. (2006) Integrin-driven actin polymerization consolidates long-term potentiation. Proc Natl Acad Sci U S A 103:5579-84
Lin, Bin; Kramar, Eniko A; Bi, Xiaoning et al. (2005) Theta stimulation polymerizes actin in dendritic spines of hippocampus. J Neurosci 25:2062-9

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