Alterations in neuronal calcium levels are associated with cognitive deficits after traumatic brain injury

Abstract

Traumatic brain injury (TBI) survivors often suffer from a post-traumatic syndrome with deficits in learning and memory. Calcium (Ca(2+)) has been implicated in the pathophysiology of TBI-induced neuronal death. However, the role of long-term changes in neuronal Ca(2+) function in surviving neurons and the potential impact on TBI-induced cognitive impairments are less understood. Here we evaluated neuronal death and basal free intracellular Ca(2+) ([Ca(2+)](i)) in acutely isolated rat CA3 hippocampal neurons using the Ca(2+) indicator, Fura-2, at seven and thirty days after moderate central fluid percussion injury. In moderate TBI, cognitive deficits as evaluated by the Morris Water Maze (MWM), occur after injury but resolve after several weeks. Using MWM paradigm we compared alterations in [Ca(2+)](i) and cognitive deficits. Moderate TBI did not cause significant hippocampal neuronal death. However, basal [Ca(2+)](i) was significantly elevated when measured seven days post-TBI. At the same time, these animals exhibited significant cognitive impairment (F(2,25)=3.43, p<0.05). When measured 30 days post-TBI, both basal [Ca(2+)](i) and cognitive functions had returned to normal. Pretreatment with MK-801 blocked this elevation in [Ca(2+)](i) and also prevented MWM deficits. These studies provide evidence for a link between elevated [Ca(2+)](i) and altered cognition. Since no significant neuronal death was observed, the alterations in Ca(2+) homeostasis in the traumatized, but surviving neurons may play a role in the pathophysiology of cognitive deficits that manifest in the acute setting after TBI and represent a novel target for therapeutic intervention following TBI.

Hypocalcaemia as a Prognostic Factor of Mortality and Morbidity in Moderate and severe Traumatic Brain Injury and its role with Protein S-100b

“…The serum levels of ionized calcium on day 3 were supplemented with protein S-100b and IL6 also on day 3 as part of the theory that calcium is diminished due to neuro-and systemic inflammation. Neuro-inflammation is likely to influence cerebral oedema, as shown in (Figures 1 and 2) [11][12][13]. As an indirect sign, patients with poor outcomes had impaired pupillary reactivity, also detected in our study as poor prognosis in the logistic regression model.…”

Development of status epilepticus, sustained calcium elevations and neuronal injury in a rat survival model of lethal paraoxon intoxication

“…We have demonstrated that CNS injuries such as SE, stroke or traumatic brain injury result in neuronal injury and protracted elevations in hippocampal [Ca 2+ ] i (Rice et al , 1998; Raza et al , 2004; Deshpande et al , 2008b; Deshpande et al , 2010). Since Ca 2+ is a major second messenger molecule, such sustained increases in its levels activate multiple signaling cascades, affect protein transcription and alter gene expression of proteins involved in controlling membrane excitability and synaptic plasticity (DeLorenzo et al , 2005).…”

“…These alterations in Ca2+ dynamics along with the associated neuronal injury are thought to underlie the chronic effects of SE on producing acquired epilepsy and behavioral and cognitive impairment (Rice et al , 1998; Raza et al , 2004; Deshpande et al , 2008b). This study will evaluate the effects of POX induced SE on the development of the Ca 2+ plateau and neuronal damage to determine if the POX SE model produces similar effects on these processes as seen with pilocarpine and DFP SE.…”

Repeated mild traumatic brain injury: potential mechanisms of damage

“…91 In moderate-severe TBI, Ca 2þ accumulation as measured by isotopelabeled Ca 2þ can persist for up to 1 wk, concomitant with memory deficits in the Morris water maze (MWM). 92 Additionally, Ca 2þ -induced depolarization of the mitochondrial membrane allows electron leakage to oxygen in the electron " Social deficits, anhedonia-like behavior, depressive-like behavior " Microglial activation, delayed Repeat þ postinjury foot shock stress: transport chain, uncoupling oxidative phosphorylation, and suppressing adenosine triphosphate (ATP) synthesis in a CCI model. 93 ATP-dependent pumps are engaged to restore TBI-induced ionic imbalances, resulting in a transient increase in cerebral glucose uptake.…”