Deficits in ERK and CREB activation in the hippocampus after traumatic brain injury

Abstract

KeywordsCREB; hippocampus; ERK; traumatic brain injury Traumatic brain injury (TBI) activates several protein kinase signaling pathways in the hippocampus that are critical for hippocampal-dependent memory formation. In particular, extracellular signal-regulated kinase (ERK), a protein kinase activated during and necessary for hippocampal-dependent learning, is transiently activated after TBI. However, TBI patients experience hippocampal-dependent cognitive deficits that occur for several months to years after the initial injury. Although basal activation levels of ERK return to sham levels within hours after TBI, we hypothesized that activation of ERK may be impaired after TBI. Adult male Sprague-Dawley rats received either sham surgery or moderate parasagittal fluidpercussion brain injury. At 2, 8, or 12 weeks after surgery, the ipsilateral hippocampi of sham surgery and TBI animals were sectioned into transverse slices. After 2 h of recovery in oxygenated artificial cerebrospinal fluid, the hippocampal slices were stimulated with glutamate or KCl depolarization, then analyzed by western blotting for phosphorylated, activated ERK and one of its downstream effectors, the transcription factor cAMP response element-binding protein (CREB). We found that activation of ERK (p<0.05) and CREB (p<0.05) after 30 s of glutamate stimulation or KCl depolarization was decreased in hippocampal slices from animals at 2, 8, or 12 weeks after TBI as compared to sham animals. Basal levels of phosphorylated or total ERK were not significantly altered at 2, 8, or 12 weeks after TBI, although basal levels of phosphorylated CREB were decreased 12 weeks posttrauma. These results suggest that TBI results in chronic signaling deficits through the ERK-CREB pathway in the hippocampus.There are an estimated 3.17 million people living with long-term disabilities due to traumatic brain injury (TBI) in the United States [51]. These neurological deficits result in the inability to perform daily living activities, return to work, and participate as productive members within their communities. Longitudinal studies assessing outcome after moderate to severe TBI have consistently found that cognitive performance is impaired for months to years after the initial trauma which significantly impedes rehabilitation [37]. Although some recovery is typically Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. observed in the first year after injury, this either slows or reverses in the following years [23,46]. In particular, memory problems are almost always observed in human TBI patients, due either to direct effect...

In vivo investigation on the potential of galangin, kaempferol and myricetin for protection of d-galactose-induced cognitive impairment

“…Recent studies have shown that the phosphorylation of CREB is necessary for the induction of the ERK-dependent plasticity (Qi et al, 2008). The activation of ERK1/2-CREB pathway is a necessary step for the learning and memory (Atkins, Falo, Alonso, Bramlett, & Dietrich, 2009;Haddad, 2005). Our western blotting observations show that galangin, kaempferol and myricetin can treat D-gal-induced impairment of ERK1/2 and CREB activations in mice hippocampus, suggesting that the three natural flavonols were able to exert neuroprotective effects via activating the phosphorylations of ERK1/2 and CREB.…”

Phosphodiesterase Inhibitors as Therapeutics for Traumatic Brain Injury

“…Unlike in the acute stages of TBI recovery where CREB phosphorylation undergoes significant upregulation, we found that phospho-CREB levels were significantly reduced at three months post-TBI in the fluid-percussion brain injury model [152]. In addition, in hippocampal slices pharmacologically stimulated with either glutamate or high potassium depolarization, we found that stimulation of phospho-CREB was significantly impaired at three months post-TBI [152]. These results suggest that increasing cAMP levels to boost CREB phosphorylation during learning may improve hippocampal synaptic function.…”

Inhibition of Eukaryotic Initiation Factor 2 Alpha Phosphatase Reduces Tissue Damage and Improves Learning and Memory after Experimental Traumatic Brain Injury

“…[1][2][3] These deficits include declarative memory and working memory dysfunction that are caused by damage to the hippocampus. [4][5][6][7][8][9][10][11] Problems with memory can interfere with post-TBI recovery, rehabilitation, and living an independent life. Both clinical and experimental studies have shown that hippocampal neurons are particularly vulnerable to TBI, and loss of these neurons can continue for weeks to months after moderate-to-severe TBI.…”

“…Further, the hippocampus, a structure within the temporal lobe, is highly vulnerable to TBI, with damage/ dysfunction of this structure shown to underlie TBI-associated learning and memory dysfunction. [4][5][6][7][8][9][10] At present, it is not known whether ER stress occurs in the hippocampus post-TBI, nor has it been examined whether lessening ER stress can improve learning and memory post-TBI. Guanabenz was recently identified as an inhibitor of growth arrest and DNA damage-inducible protein 34 (an eIF2a phosphatase), and its exposure to HeLa cells increases eIF2a phosphorylation.…”