EXCEED THE SPACE PROVIDED. Transient, but severe global ischemia, observed in patients during cardiac arrest and cardiac surgery or induced experimentally in animals, induces selective and delayed neurodegeneration. Pyramidal cells in CA1 are the most sensitive; CA3 and granule cells of the dentate gyrus (DG) are resistant to ischemic damage, and GABAergic interneurons in CA1 also survive. The molecular mechanisms underlying this pattern of neuronal death are not well understood. The proposed research aims to study the role of gap junctions during the several days of 'maturation' of neuronal injury after global ischemia. Recent findings from this laboratory indicate that global ischemia triggers a selective upregulation of Cx36 (and Cx32) protein expression in GABAergic interneurons of the vulnerable CA1 at times prior to the onset of neuronal death, consistent with a role in the survival of these neurons. Moreover, CA1 neurons in Cx32 (Y/-) mice exhibit enhanced vulnerability to global ischemia-induced neuronal death. These data suggest that increased inhibition of pyramidal cells through synchronization of inhibitory interneurons may be neuroprotective. Gap junctions between astrocytes are also thought to have a role in postischemic neuronal death. Dying cells can kill resistant neighboring glial cells via glial 'fratricide' (bystander death) and thereby propagate injury to neighboring regions. On the other hand, gap junctional coupling of astrocytes mediates metabolic cooperation among them and attenuates neuronal death in models of oxidative stress. The underlying hypothesis of this proposal is that gap junctions play important roles in determining neuronal death and survival following global ischemia. The research plan for the next five years focuses on changes in the abundance, distribution and molecular and biophysical properties of brain gap junctions following neurological insult.
Specific Aims are 1. Characterize ischemia-induced alterations in connexin expression and gap junction properties in the vulnerable CA1 and resistant CA3 and dentate gyrus of rats and mice. Experiments will examine global ischemia-induced changes in coupling of inhibitory interneurons and expression of connexin proteins by immunocytochemistry and Western blotting and of connexin mRNAs by in situ hybridization and. Experiments will determine the effects of acute knockdown of specific connexins by antisense oligonucleotides on neuronal vulnerability and will examine neuronal vulnerability in Cx32(Y/-) mice, Cx36(-/-) mice and mice deficient in astrocyte Cx43. 2. Examine effects of oxygen/glucose deprivation on hippocampal slice cultures by immunocytochemistry, in situ hybridization and electrophysiological methods. To examine ischemia-induced changes in gap junction properties in acute slices and organotypic hippocampal slice cultures by electrophysiological methods and image analysis. The proposed research is expected to impact on the development of new treatment strategies for intervention in global ischemia, a debilitating and often fatal trauma associated with cardiac arrest in humans. Moreover, this study has important implications for research on other neurodegenerative disorders including focal ischemia, epilepsy, AIDS encephalopathy, and Alzheimer's disease. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045287-03
Application #
6828345
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Jacobs, Tom P
Project Start
2002-12-15
Project End
2007-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
3
Fiscal Year
2005
Total Cost
$356,963
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Garré, Juan Mauricio; Yang, Guang; Bukauskas, Feliksas F et al. (2017) An Acute Mouse Spinal Cord Slice Preparation for Studying Glial Activation ex vivo. Bio Protoc 7:
Garré, Juan Mauricio; Yang, Guang; Bukauskas, Feliksas F et al. (2016) FGF-1 Triggers Pannexin-1 Hemichannel Opening in Spinal Astrocytes of Rodents and Promotes Inflammatory Responses in Acute Spinal Cord Slices. J Neurosci 36:4785-801
Stetler, R Anne; Gao, Yanqin; Leak, Rehana K et al. (2016) APE1/Ref-1 facilitates recovery of gray and white matter and neurological function after mild stroke injury. Proc Natl Acad Sci U S A 113:E3558-67
Wang, Guohua; Shi, Yejie; Jiang, Xiaoyan et al. (2015) HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3?/PTEN/Akt axis. Proc Natl Acad Sci U S A 112:2853-8
Riquelme, Manuel A; Cea, Luis A; Vega, José L et al. (2013) The ATP required for potentiation of skeletal muscle contraction is released via pannexin hemichannels. Neuropharmacology 75:594-603
Eugenin, E A; King, J E; Hazleton, J E et al. (2011) Differences in NMDA receptor expression during human development determine the response of neurons to HIV-tat-mediated neurotoxicity. Neurotox Res 19:138-48
Nolt, Mark J; Lin, Ying; Hruska, Martin et al. (2011) EphB controls NMDA receptor function and synaptic targeting in a subunit-specific manner. J Neurosci 31:5353-64
Palacios-Prado, Nicolas; Briggs, Stephen W; Skeberdis, Vytenis A et al. (2010) pH-dependent modulation of voltage gating in connexin45 homotypic and connexin45/connexin43 heterotypic gap junctions. Proc Natl Acad Sci U S A 107:9897-902
Saez, Juan C; Schalper, Kurt A; Retamal, Mauricio A et al. (2010) Cell membrane permeabilization via connexin hemichannels in living and dying cells. Exp Cell Res 316:2377-89
Lau, C Geoffrey; Takayasu, Yukihiro; Rodenas-Ruano, Alma et al. (2010) SNAP-25 is a target of protein kinase C phosphorylation critical to NMDA receptor trafficking. J Neurosci 30:242-54

Showing the most recent 10 out of 28 publications