TY - JOUR
T1 - Activation of calcium/calmodulin-dependent protein kinases after traumatic brain injury
AU - Atkins, Coleen M.
AU - Chen, Shaoyi
AU - Alonso, Ofelia F.
AU - Dietrich, W. Dalton
AU - Hu, Bing Ren
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2006/12/8
Y1 - 2006/12/8
N2 - A prominent cognitive impairment after traumatic brain injury (TBI) is hippocampal-dependent memory loss. Although the histopathologic changes in the brain are well documented after TBI, the underlying biochemical mechanisms that contribute to memory loss have yet to be thoroughly delineated. Thus, we determined if calcium/calmodulin-dependent protein kinases (CaMKs), known to be necessary for the formation of hippocampal-dependent memories, are regulated after TBI. Sprague-Dawley rats underwent moderate parasagittal fluid-percussion brain injury on the right side of the parietal cortex. The ipsilateral hippocampus and parietal cortex were Western blotted for phosphorylated, activated α-calcium/calmodulin-dependent protein kinase II (α-CaMKII), CaMKIV, and CaMKI. α-Calcium/calmodulin-dependent protein kinase II was activated in membrane subcellular fractions from the hippocampus and parietal cortex 30 mins after TBI. CaMKI and CaMKIV were activated in a more delayed manner, increasing in phosphorylation 1 h after TBI. The increase in activated α-CaMKII in membrane fractions was accompanied by a decrease in cytosolic total α-CaMKII, suggesting redistribution to the membrane. Using confocal microscopy, we observed that α-CaMKII was activated within hippocampal neurons of the dentate gyrus, CA3, and CA1 regions. Two downstream substrates of α-CaMKII, the AMPA-type glutamate receptor GluR1, and cytoplasmic polyadenylation element-binding protein, concomitantly increased in phosphorylation in the hippocampus and cortex 1 h after TBI. These results demonstrate that several of the biochemical cascades that subserve memory formation are activated unselectively in neurons after TBI. As memory formation requires activation of CaMKII signaling pathways at specific neuronal synapses, unselective activation of CaMKII signaling in all synapses may disrupt the machinery for memory formation, resulting in memory loss after TBI.
AB - A prominent cognitive impairment after traumatic brain injury (TBI) is hippocampal-dependent memory loss. Although the histopathologic changes in the brain are well documented after TBI, the underlying biochemical mechanisms that contribute to memory loss have yet to be thoroughly delineated. Thus, we determined if calcium/calmodulin-dependent protein kinases (CaMKs), known to be necessary for the formation of hippocampal-dependent memories, are regulated after TBI. Sprague-Dawley rats underwent moderate parasagittal fluid-percussion brain injury on the right side of the parietal cortex. The ipsilateral hippocampus and parietal cortex were Western blotted for phosphorylated, activated α-calcium/calmodulin-dependent protein kinase II (α-CaMKII), CaMKIV, and CaMKI. α-Calcium/calmodulin-dependent protein kinase II was activated in membrane subcellular fractions from the hippocampus and parietal cortex 30 mins after TBI. CaMKI and CaMKIV were activated in a more delayed manner, increasing in phosphorylation 1 h after TBI. The increase in activated α-CaMKII in membrane fractions was accompanied by a decrease in cytosolic total α-CaMKII, suggesting redistribution to the membrane. Using confocal microscopy, we observed that α-CaMKII was activated within hippocampal neurons of the dentate gyrus, CA3, and CA1 regions. Two downstream substrates of α-CaMKII, the AMPA-type glutamate receptor GluR1, and cytoplasmic polyadenylation element-binding protein, concomitantly increased in phosphorylation in the hippocampus and cortex 1 h after TBI. These results demonstrate that several of the biochemical cascades that subserve memory formation are activated unselectively in neurons after TBI. As memory formation requires activation of CaMKII signaling pathways at specific neuronal synapses, unselective activation of CaMKII signaling in all synapses may disrupt the machinery for memory formation, resulting in memory loss after TBI.
KW - CaMKI
KW - CaMKII
KW - CaMKIV
KW - CPEB
KW - GluR1
KW - Traumatic brain injury
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U2 - 10.1038/sj.jcbfm.9600301
DO - 10.1038/sj.jcbfm.9600301
M3 - Article
C2 - 16570077
AN - SCOPUS:33751346802
VL - 26
SP - 1507
EP - 1518
JO - Journal of Cerebral Blood Flow and Metabolism
JF - Journal of Cerebral Blood Flow and Metabolism
SN - 0271-678X
IS - 12
ER -