The integrins are heterodimer trans-membrane cell adhesion receptors with extracellular domains that bind extracellular matrix and cell surface proteins and cytoplasmic domains that are linked to cytoskeletal elements and activate signal transduction pathways. Little is known about the distribution, regulation and function of integrin proteins in adult brain although recent findings implicate these receptors in synaptic plasticity. Preliminary studies by the applicant have demonstrated that integrin subunit expression is high in areas of synaptogenesis and is regulated by neuronal activity. Moreover, pilot studies indicate that manipulation of integrin signaling alters the expression of neurotrophin genes. Together with previous reports of integrin involvement in long term potentiation, these findings suggest that the integrins are active in the mature brain and are associated with activity-dependent gene regulation and neuronal plasticity. The goals of the proposed research are to test this hypothesis. There are five specific aims.
Specific Aim 1 will use in situ hybridization to map integrin subunit mRNA expression in brain and test the hypothesis that subunits are differentially distributed across forebrain systems.
aims 2 and 3 will determine if synaptic activity regulates integrin turnover in adult brain. Studies will determine if activity induces mRNA expression (Aim 2) and protease-dependent degradation (Aim 3) of hippocampal beta1 integrin.
Aim 4 will test the hypothesis that pools of latent integrins exist in brain and these are activated by stimuli associated with intense physiological activity. Antisera specific for the active conformation of beta 1 integrin will be used to test the effects of electrical stimulation and proposed signaling molecules active in association with intense synaptic activity. Activation of latent integrins is a route used by various biological signals to modify anatomy and genomic expression in target cells but there is no evidence relating to the possible use of this mechanism in brain. The fifth aim is to determine if integrin receptors mediate or modulate activity-dependent changes in neurotrophic factor expression. Together, these studies will provide the first analysis in brain of the distribution, responsivity and trophic functions of a class of receptors critical to signal transduction in the periphery and may provide evidence for a novel mechanism of neurotrophic factor gene regulation associated with maturational changes in brain neurotrophism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037799-04
Application #
6393976
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Mamounas, Laura
Project Start
1998-07-01
Project End
2002-12-31
Budget Start
2001-07-01
Budget End
2002-12-31
Support Year
4
Fiscal Year
2001
Total Cost
$158,363
Indirect Cost
Name
University of California Irvine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
161202122
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
Brewster, Amy L; Bernard, Joie A; Gall, Christine M et al. (2005) Formation of heteromeric hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the hippocampus is regulated by developmental seizures. Neurobiol Dis 19:200-7

Showing the most recent 10 out of 22 publications