Connexins in Ischemia-Induced Neuronal Death

Project: Research project

Project Details


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.
Effective start/end date12/15/0211/30/08


  • Clinical Neurology
  • Neurology


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