This application seeks funds for the continuation of a project aimed at studying the biological signals that induce a reactive state in astrocytes in vivo. The model system that has been exploited during the current funding period is primarily the hippocampal formation of the rat. Astrocytic responses are induced by lesions, either surgical (aspiration of entorhinal cortex) or electrical (seizures or spreading depression). The response that has been measured is the up-regulation of GFAP and GFAP mRNA. During the current funding period, the principal investigator has determined that electrolytic brain lesions lead to an astrocytic response, measured as a marked increase in GFAP.This increase is not attenuated by blocking all neuronal activity in the affected area (by injection of TTX), and the TTX block alone has no effect. At the same time """"""""intense stimulation"""""""" of entorhinal cortex (i.e., electrical activity) does lead to a modest increase in GFAP. The timing of the increase has been studied in detail as has its unilateral vs. bilateral nature. The role of """"""""diffusible gliotrophic substances"""""""" has been studied by placing gel plegets directly on the cerebral cortex of experimental animals. Pledgets that have been pretreated with saline (controls) induce no response. By contrast, the experimental gels that had undergone a 24 hr incubation in a lesion induced cavity in a donor rat induced a substantial GFAP response. The role of degeneration debris in stimulating astrocytic responses was measured in a clever system, the Ola mouse strain (an inbred strain in which Wallerian degeneration occurs on a much delayed time course). The GFAP response in the denervated region was delayed by the same degree as the degeneration. The role of high [K+] in the GFAP induction was investigated by putting K+-gelfoam on the cortex and getting a huge response. There was an increase in cerebral cortex as well, but on a slower time base. In each, the extent of the GFAP rise was related to whether the resulting seizures were accompanied by spreading depression.The sprouting of cholinergic afferents, a normal part of the hippocampal response to entorhinal cortex lesions was blocked by seizures induced in the early post-lesion period.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS029875-04
Application #
2267984
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1991-08-01
Project End
1998-07-31
Budget Start
1994-09-01
Budget End
1995-08-31
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Virginia
Department
Neurosciences
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Medrano, S; Steward, O (2001) Differential mRNA localization in astroglial cells in culture. J Comp Neurol 430:56-71
Schauwecker, P E; Ramirez, J J; Steward, O (2000) Genetic dissection of the signals that induce synaptic reorganization. Exp Neurol 161:139-52
Steward, O; Kelley, M S; Schauwecker, P E (1997) Signals that regulate astroglial gene expression: induction of GFAP mRNA following seizures or injury is blocked by protein synthesis inhibitors. Exp Neurol 148:100-9
Steward, O; Trimmer, P A (1997) Genetic influences on cellular reactions to CNS injury: the reactive response of astrocytes in denervated neuropil regions in mice carrying a mutation (Wld(S)) that causes delayed Wallerian degeneration. J Comp Neurol 380:70-81
Schauwecker, P E; Steward, O (1997) Genetic influences on cellular reactions to brain injury: activation of microglia in denervated neuropil in mice carrying a mutation (Wld(S)) that causes delayed Wallerian degeneration. J Comp Neurol 380:82-94
Fujiki, M; Steward, O (1997) High frequency transcranial magnetic stimulation mimics the effects of ECS in upregulating astroglial gene expression in the murine CNS. Brain Res Mol Brain Res 44:301-8
Schauwecker, P E; Steward, O (1997) Genetic determinants of susceptibility to excitotoxic cell death: implications for gene targeting approaches. Proc Natl Acad Sci U S A 94:4103-8
Kelley, M S; Steward, O (1996) The role of postlesion seizures and spreading depression in the upregulation of glial fibrillary acidic protein mRNA after entorhinal cortex lesions. Exp Neurol 139:83-94
Kelley, M S; Steward, O (1996) The process of reinnervation in the dentate gyrus of adult rats: physiological events at the time of the lesion and during the early postlesion period. Exp Neurol 139:73-82
Bonthius, D J; Lothman, E W; Steward, O (1995) The role of extracellular ionic changes in upregulating the mRNA for glial fibrillary acidic protein following spreading depression. Brain Res 674:314-28

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