Glutamate transport is critical for the maintenance of low extracellular glutamate and dysregulation of transporters can lead to acute and chronic neurodegeneration. The astroglial transporter EAAT2/GLT1 is the dominant glutamate transporter, accounting for up to 95% of all CNS glutamate transport. Loss of EAAT2 occurs in human diseases and disease models such as ALS, and can contribute to neuronal and astroglial dysfunction and cell death. Recently an alternative splice variant of EAAT2/GLT1, known as EAAT2b/GLT1b, was identified, and early studies suggest it may be present in neurons. Our preliminary data suggest EAAT2b/GLT1b protein expression is regulated and enhanced by neural injury and neurological disease, leading a unique high-level expression in neurons- rather than glia. In this proposal- we will more fully explore the basic biology of this potentially important transport splice variant and its relationship to neuronal/astroglial injury. We hypothesize that EAAT2b/GLT1 is functionally expressed in neural injury as a protective reaction or compensation for the dysregulation of astroglial glutamate transport and may be synaptically active. To test this hypothesis we will: 1) Investigate the altered regional and cellular expression of EAAT2b/GLT1b in ALS and ALS models; 2) Study the function and expression of EAAT2b/GLTb under conditions of neuronal/glial stress; and 3) Analyze the function of GLT1b in neurons vs. astroglia, thru targeted deletion of GLT1/GLT1b from neurons. These studies will help determine if the altered expression of GLT1b in disease is an important physiological response. They will also provide basic physiological properties of the neuronal versus glial pools of GLT1 and GLT1b.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS033958-13
Application #
7341066
Study Section
Special Emphasis Panel (ZRG1-CDIN (01))
Program Officer
Refolo, Lorenzo
Project Start
1995-05-01
Project End
2009-11-30
Budget Start
2007-12-01
Budget End
2008-11-30
Support Year
13
Fiscal Year
2008
Total Cost
$424,354
Indirect Cost
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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