期刊
JOURNAL OF NEUROTRAUMA
卷 29, 期 6, 页码 1197-1208出版社
MARY ANN LIEBERT INC
DOI: 10.1089/neu.2011.2261
关键词
LY 379268; DL-threo-beta-benzyloxyaspartate; omega-conotoxin; (S)-4-carboxyphenylglycine
资金
- USPHS [DA017186, NS3978, AG013494]
- NSF (ERC) [EEC-0310723]
- DARPA [N6601-09-2080]
- Kentucky Spinal Cord and Head Injury Research Trust [7-11]
- [F31NS067899]
Disrupted regulation of extracellular glutamate in the central nervous system contributes to and can exacerbate the acute pathophysiology of traumatic brain injury (TBI). Previously, we reported increased extracellular glutamate in the striatum of anesthetized rats 2 days after diffuse brain injury. To determine the mechanism(s) responsible for increased extracellular glutamate, we used enzyme-based microelectrode arrays (MEAs) coupled with specific pharmacological agents targeted at in vivo neuronal and glial regulation of extracellular glutamate. After TBI, extracellular glutamate was significantly increased in the striatum by (similar to 90%) averaging 4.1 +/- 0.6 mu M compared with sham 2.2 +/- 0.4 mu M. Calcium-dependent neuronal glutamate release, investigated by local application of an N-type calcium channel blocker, was no longer a significant source of extracellular glutamate after TBI, compared with sham. In brain-injured animals, inhibition of glutamate uptake with local application of an excitatory amino acid transporter inhibitor produced significantly greater increase in glutamate spillover (similar to 65%) from the synapses compared with sham. Furthermore, glutamate clearance measured by locally applying glutamate into the extracellular space revealed significant reductions in glutamate clearance parameters in brain-injured animals compared with sham. Taken together, these data indicate that disruptions in calcium-mediated glutamate release and glial regulation of extracellular glutamate contribute to increased extracellular glutamate in the striatum 2 days after diffuse brain injury. Overall, these data suggest that therapeutic strategies used to regulate glutamate release and uptake may improve excitatory circuit function and, possibly, outcomes following TBI.
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