Depression following traumatic brain injury in mice is associated with down-regulation of hippocampal astrocyte glutamate transporters by thrombin

Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism
Chunshu PiaoMark S Wainwright

Abstract

Depression after traumatic brain injury (TBI) is common but the mechanisms by which TBI causes depression are unknown. TBI decreases glutamate transporters GLT-1 and GLAST and allows extravasation of thrombin. We examined the effects of thrombin on transporter expression in primary hippocampal astrocytes. Application of a PAR-1 agonist caused down-regulation of GLT-1, which was prevented by inhibition of Rho kinase (ROCK). To confirm these mechanisms in vivo, we subjected mice to closed-skull TBI. Thrombin activity in the hippocampus increased one day following TBI. Seven days following TBI, expression of GLT-1 and GLAST was reduced in the hippocampus, and this was prevented by administration of the PAR-1 antagonist SCH79797. Inhibition of ROCK attenuated the decrease in GLT-1, but not GLAST, after TBI. We measured changes in glutamate levels in the hippocampus seven days after TBI using an implanted biosensor. Stress-induced glutamate levels were significantly increased following TBI and this was attenuated by treatment with the ROCK inhibitor fasudil. We quantified depressive behavior following TBI and found that inhibition of PAR-1 or ROCK decreased these behaviors. These results identify a novel mechanism by which TBI resul...Continue Reading

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Citations

Aug 6, 2019·Frontiers in Psychiatry·Luca SteardoPasquale De Fazio
Mar 6, 2021·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Cen YangLize Xiong
Mar 5, 2021·Reviews in the Neurosciences·Marc FakhouryNada Lawand
May 29, 2020·Neuropharmacology·Matjaž StenovecRobert Zorec
May 1, 2021·Biomolecules·Nathan A ShlobinChaim G Pick

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Methods Mentioned

BETA
fluorescence microscopy
ICE
electrophoresis
Assay
biosensor
biosensors

Software Mentioned

Carestream Molecular Imaging
GLAST
Carestream
ImageJ
EthoVision
GraphPad
ARRIVE
GraphPad Prism

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