In vitro status epilepticus causes sustained elevation of intracellular calcium levels in hippocampal neurons

Pal, Shubhro; Sombati, Sompong; Limbrick, David D.; DeLorenzo, Robert J.

doi:10.1016/s0006-8993(99)02035-1

Cited by 81 publications

(68 citation statements)

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“…In addition, SE without the development of AE did not result in long-term changes in [Ca 2ϩ ] i , further indicating a relationship between the development of AE and the alteration in Ca 2ϩ dynamics. These results in an intact animal model of AE support in vitro models of AE that directly demonstrated the role of elevated [Ca 2ϩ ] i in producing spontaneous recurrent seizures after SE and glutamate excitotoxic injuries in hippocampal neurons (8)(9)(10)(11)(12)(13). The in vitro models of AE allow for a rigorous control of environmental conditions to directly demonstrate the role of altered Ca 2ϩ dynamics in causing AE.…”

Section: Discussionsupporting

confidence: 64%

“…The molecular basis for developing AE is still not completely understood. However, there is growing evidence from the SE and glutamate injury-induced models of AE that elevated intracellular calcium concentration ([Ca 2ϩ ] i ) and altered Ca 2ϩ -homeostatic mechanisms (Ca 2ϩ dynamics) may play a role in the development of AE (6,(8)(9)(10)(11)(12)(13). In addition, altered Ca 2ϩ dynamics have been observed in the hippocampus of chronic epileptic animals as long as 1 year after the induction of seizures in the in vivo pilocarpine model of AE (14).…”

Section: Alterations In Hippocampal Neuronalmentioning

confidence: 99%

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Evidence that injury-induced changes in hippocampal neuronal calcium dynamics during epileptogenesis cause acquired epilepsy

Raza

Blair

Sombati

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Alterations in hippocampal neuronalneuronal plasticity ͉ pilocarpine model ͉ calcium homeostasis ͉ seizure E pilepsy is one of the most common neurological disorders (1), and Ϸ40% of epilepsies are acquired, meaning that the epileptic condition is acquired through an injury to the nervous system (2, 3). Epileptogenesis is the process by which an injury such as status epilepticus (SE), stroke, or traumatic brain injury produces long-term plasticity changes in neurons, resulting in spontaneous recurrent seizures [acquired epilepsy (AE)] in previously normal brain tissue (4-6). AE develops in three phases: injury (brain insult), epileptogenesis (latency), and, finally, chronic epilepsy (spontaneous recurrent seizure) (7). The molecular basis for developing AE is still not completely understood. However, there is growing evidence from the SE and glutamate injury-induced models of AE that elevated intracellular calcium concentration ([Ca 2ϩ ] i ) and altered Ca 2ϩ -homeostatic mechanisms (Ca 2ϩ dynamics) may play a role in the development of AE (6,(8)(9)(10)(11)(12)(13). In addition, altered Ca 2ϩ dynamics have been observed in the hippocampus of chronic epileptic animals as long as 1 year after the induction of seizures in the in vivo pilocarpine model of AE (14). This model of AE shares many of the clinical and pathophysiological characteristics of partial-complex or temporal-lobe epilepsy in humans (14-19). The hippocampus has been shown to be the focus for many of the plasticity, pathophysiological, and epileptogenic alterations in the pilocarpine model of AE (14-19). Thus, if Ca 2ϩ is involved as a second messenger in the inductions and maintenance of AE in the pilocarpine model, it would be expected that Ca 2ϩ dynamics should be altered immediately after SE and in the three phases of the development of AE.This study was undertaken to determine whether hippocampal neuronal Ca 2ϩ dynamics are altered immediately after SE and in the three phases of the development of AE.Ca 2ϩ dynamics were evaluated in acutely isolated CA1 hippocampal, frontal, and occipital neurons at several time points during the injury, epileptogenesis, and chronic-epilepsy phases of AE. The effects of NMDA receptor inhibition by (ϩ)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK801) on both the development of seizures and Ca 2ϩ dynamics were determined. Comparisons of sham (salinetreated), pilocarpine without SE, and pilocarpine with SE but without AE control animals with SE animals with AE indicated that Ca 2ϩ dynamics were significantly altered during the development of AE and that both changes in Ca 2ϩ dynamics and the development of AE could be blocked by inhibition of the NMDA receptor during SE. The results demonstrate that altered Ca 2ϩ dynamics were associated with the development of AE and that inhibition of these changes in Ca 2ϩ dynamics was associated with the inhibition of the development of AE. The results provide direct evidence that Ca 2ϩ dynamics are significantly altered during epileptogenesis and ...

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Section: Discussionsupporting

confidence: 64%

Section: Alterations In Hippocampal Neuronalmentioning

confidence: 99%

Evidence that injury-induced changes in hippocampal neuronal calcium dynamics during epileptogenesis cause acquired epilepsy

Raza

Blair

Sombati

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

111

135

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“…Although MK801 and APV have no effect on the low-Mg 2+ -induced continuous spike firing of this model, these NMDA antagonists do block the development of SREDs DeLorenzo et al, 1998). These drugs also significantly reduce the sustained elevations in [Ca 2+ ] i that occur during epileptogenic low-Mg 2+ -induced spike firing Pal et al, 1999;Fig. 8 (Fig.…”

Section: Elevated Levels Of Free [Ca 2+ ] I In the Acute And Epileptomentioning

confidence: 72%

“…Using the low-magnesium (Mg 2+ ) model of SE in vitro, it was possible to provide the first direct evidence that SE causes acute and prolonged increases in [Ca 2+ ] i ( Fig. 1 and Fig 2; Pal et al, 1999). These studies simultaneously measured in real time both [Ca 2+ ] i and electrophysiological parameters to directly demonstrate the correlation between increased [Ca 2+ ] i and seizure activity.…”

Section: Status Epilepticus: Causes Neuronal Injury and Increased Glumentioning

confidence: 97%

Cellular mechanisms underlying acquired epilepsy: The calcium hypothesis of the induction and maintainance of epilepsy

DeLorenzo

Sun

Deshpande

2005

Pharmacology & Therapeutics

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Epilepsy is one of the most common neurological disorders. Although epilepsy can be idiopathic, it is estimated that up to 50% of all epilepsy cases are initiated by neurological insults and are called acquired epilepsy (AE). AE develops in 3 phases: (1) the injury (central nervous system [CNS] insult), (2) epileptogenesis (latency), and (3) the chronic epileptic (spontaneous recurrent seizure) phases. Status epilepticus (SE), stroke, and traumatic brain injury (TBI) are 3 major examples of common brain injuries that can lead to the development of AE. It is especially important to understand the molecular mechanisms that cause AE because it may lead to innovative strategies to prevent or cure this common condition. Recent studies have offered new insights into the cause of AE and indicate that injury-induced alterations in intracellular calcium concentration levels [Ca 2+ ] i and calcium homeostatic mechanisms play a role in the development and maintenance of AE. The injuries that cause AE are different, but they share a common molecular mechanism for producing brain damage -an increase in extracellular glutamate concentration that causes increased intracellular neuronal calcium, leading to neuronal injury and/or death. Neurons that survive the injury induced by glutamate and are exposed to increased [Ca 2+ ] i are the cellular substrates to develop epilepsy because dead cells do not seize. The neurons that survive injury sustain permanent long-term plasticity changes in [Ca 2+ ] i and calcium homeostatic mechanisms that are permanent and are a prominent feature of the epileptic phenotype. In the last several years, evidence has accumulated indicating that the prolonged alteration in neuronal calcium dynamics plays an important role in the induction and maintenance of the prolonged neuroplasticity changes underlying the epileptic phenotype. Understanding the role of calcium as a second messenger in the induction and maintenance of epilepsy may provide novel insights into therapeutic advances that will prevent and even cure AE.

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“…Calcium plays a fundamental role in neurons as a second messenger governing cellular functions such as differentiation and growth, membrane excitability, exocytosis, and synaptic activity (Delorenzo et al, 2005). It has been shown that some of the long-term alterations in Ca 2+ homeostatic mechanisms observed after epileptogenesis are mediated by long-term alterations in the function of the endoplasmic reticulum Ca 2+ ATPase and IP 3 Ca 2+ induced Ca 2+ release system (Pal et al, 1999;Pal et al, 2000;Parsons et al, 2000;Pal et al, 2001;Parsons et al, 2001;Parsons et al, 2004). In addition, calbindin-D28k is one of the major calcium binding proteins in brain and previous studies have reported the vulnerability of calbindin-positive neurons in the dentate granule cell layer of the hippocampus in epilepsy (Scharfman et al, 2002;Krsek et al, 2004;Tang et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Long-term decrease in calbindin-D28K expression in the hippocampus of epileptic rats following pilocarpine-induced status epilepticus

et al. 2008

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SummaryAcquired epilepsy (AE) is characterized by spontaneous recurrent seizures and long-term changes that occur in surviving neurons following an injury such as status epilepticus (SE). Long-lasting alterations in hippocampal Ca 2+ homeostasis have been observed in both in vivo and in vitro models of AE. One major regulator of Ca 2+ homeostasis is the neuronal calcium binding protein, calbindinD28k that serves to buffer and transport Ca 2+ ions. This study evaluated the expression of hippocampal calbindin levels in the rat pilocarpine model of AE. Calbindin protein expression was reduced over 50% in the hippocampus in epileptic animals. This decrease was observed in the pyramidal layer of CA1, stratum lucidum of CA3, hilus, and stratum granulosum and stratum moleculare of the dentate gyrus when corrected for cell loss. Furthermore, calbindin levels in individual neurons were also significantly reduced. In addition, the expression of calbindin mRNA was decreased in epileptic animals. Time course studies demonstrated that decreased calbindin expression was initially present 1 month following pilocarpine-induced SE and lasted for up to 2 years after the initial episode of SE. The results indicate that calbindin is essentially permanently decreased in the hippocampus in AE. This decrease in hippocampal calbindin may be a major contributing factor underlying some of the plasticity changes that occur in epileptogenesis and contribute to the alterations in Ca 2+ homeostasis associated with AE.

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In vitro status epilepticus causes sustained elevation of intracellular calcium levels in hippocampal neurons

Cited by 81 publications

References 50 publications

Evidence that injury-induced changes in hippocampal neuronal calcium dynamics during epileptogenesis cause acquired epilepsy

Evidence that injury-induced changes in hippocampal neuronal calcium dynamics during epileptogenesis cause acquired epilepsy

Cellular mechanisms underlying acquired epilepsy: The calcium hypothesis of the induction and maintainance of epilepsy

Long-term decrease in calbindin-D28K expression in the hippocampus of epileptic rats following pilocarpine-induced status epilepticus

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