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The pathophysiology of traumatic brain injury in alpha7 nicotinic cholinergic receptor knockout mice
Matthew L Kelso1, Jeanne M Wehner, Allan C Collins
1College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
Abstract:
The alpha7 nicotinic cholinergic receptor is a ligand-gated ion channel with calcium permeability similar to that of ionotrophic glutamate receptors. Previous studies from our laboratory have implicated changes in expression alpha7 nicotinic cholinergic receptors in the pathophysiology of traumatic brain injury (TBI). In rats, TBI causes a time-dependent and significant decrease in cortical and hippocampal alpha-[(125)I]-bungarotoxin (BTX) binding. We have postulated that deficits in alpha7 expression may contribute to TBI-induced cognitive impairment and that nicotinic receptor agonists can reverse alpha7 binding deficits and result in significant cognitive improvement compared to saline-treated controls. Thus, alpha7 nAChRs could be involved in a form of cholinergically mediated excitotoxicity following brain injury. In the current study, wild-type, heterozygous and null mutant mice were employed to test the hypothesis that genotypic depletion of the alpha7 receptor would render animals less sensitive to tissue loss and brain inflammation following experimental brain injury. Mice were anesthetized and subjected to a 0.5-mm cortical contusion injury of the somatosensory cortex. Brain inflammation, changes in nicotinic receptor expression and cortical tissue sparing were evaluated in wild-type, heterozygous and homozygous mice 1 week following TBI. In wild-type mice, brain injury caused a significant decrease in BTX binding in several hippocampal regions, consistent with what we have measured in rat brain following TBI. However, there were no genotypic differences in cortical tissue sparing or brain inflammation in this experiment. Although the results of this study were largely negative, it is still plausible that changes in the activity/expression of native alpha7 receptors contribute to pathophysiology following TBI. However, when null mutant mice develop in the absence of central alpha7 expression, it is possible that compensatory changes occur that confound the results obtained.
Insights
Traumatic brain injury (TBI) decreases alpha7 nicotinic receptor binding. Genetically depleting alpha7 nicotinic acetylcholine receptors (nAChRs) in mice did not alter brain inflammation or tissue loss following TBI, suggesting compensatory mechanisms may be involved.
Area of Science:
- Neuroscience
- Neuropharmacology
- Neuroinflammation
Background:
- Alpha7 nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels implicated in traumatic brain injury (TBI) pathophysiology.
- Previous studies show TBI decreases alpha7 nAChR binding in rats, suggesting a role in cognitive impairment.
Purpose of the Study:
- To investigate if genotypic depletion of alpha7 nAChRs influences sensitivity to tissue loss and brain inflammation post-TBI.
- To determine if reduced alpha7 nAChR expression impacts TBI outcomes.
Main Methods:
- Wild-type, heterozygous, and null mutant mice were subjected to a cortical contusion injury.
- Brain inflammation, nicotinic receptor expression, and cortical tissue sparing were assessed one week post-TBI.
Main Results:
- TBI significantly decreased alpha-[(125)I]-bungarotoxin (BTX) binding in wild-type mouse hippocampus, confirming previous findings.
- No genotypic differences in cortical tissue sparing or brain inflammation were observed between wild-type, heterozygous, and null mutant mice.
Conclusions:
- Genotypic depletion of alpha7 nAChRs did not alter TBI-induced tissue loss or inflammation in this model.
- Compensatory mechanisms in null mutant mice may confound results, and the role of alpha7 nAChRs in TBI pathophysiology warrants further investigation.
