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Stretch‐induced injury in organotypic hippocampal slice cultures reproduces in vivo post‐traumatic neurodegeneration: role of glutamate receptors and voltage‐dependent calcium channels
Author(s) -
Cater Heather L.,
Gitterman Daniel,
Davis Susan M.,
Benham Christopher D.,
Morrison Barclay,
Sundstrom Lars E.
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.04379.x
Subject(s) - neuroprotection , nmda receptor , traumatic brain injury , neurodegeneration , neuroscience , hippocampal formation , glutamate receptor , ampa receptor , in vivo , pharmacology , medicine , biology , anesthesia , receptor , pathology , disease , microbiology and biotechnology , psychiatry
Abstract The relationship between an initial mechanical event causing brain tissue deformation and delayed neurodegeneration in vivo is complex because of the multiplicity of factors involved. We have used a simplified brain surrogate based on rat hippocampal slices grown on deformable silicone membranes to study stretch‐induced traumatic brain injury. Traumatic injury was induced by stretching the culture substrate, and the biological response characterized after 4 days. Morphological abnormalities consistent with traumatic injury in humans were widely observed in injured cultures. Synaptic function was significantly reduced after a severe injury. The N ‐methyl‐D‐aspartate (NMDA) receptor antagonist MK‐801 attenuated neuronal damage, prevented loss of microtubule‐associated protein 2 immunoreactivity and attenuated reduction of synaptic function. In contrast, the NMDA receptor antagonists 3‐[( R )‐2‐carboxypiperazin‐4‐yl]‐propyl‐1‐phosphonic acid (CPP) and GYKI53655, were neuroprotective in a moderate but not a severe injury paradigm. Nifedipine, an L‐type voltage‐dependent calcium channel antagonist was protective only after a moderate injury, whereas ω‐conotoxin attenuated damage following severe injury. These results indicate that the mechanism of damage following stretch injury is complex and varies depending on the severity of the insult. In conclusion, the pharmacological, morphological and electrophysiological responses of organotypic hippocampal slice cultures to stretch injury were similar to those observed in vivo . Our model provides an alternative to animal testing for understanding the mechanisms of post‐traumatic delayed cell death and could be used as a high‐content screen to discover neuroprotective compounds before advancing to in vivo models.