Long-term alteration of calcium homeostatic mechanisms in the pilocarpine model of temporal lobe epilepsy

Raza, Mohsin; Pal, Shubhro; Rafiq, Azhar; DeLorenzo, Robert J.

doi:10.1016/s0006-8993(01)02127-8

Cited by 93 publications

(105 citation statements)

References 59 publications

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“…In this study, calbindin expression observed at early time points (1 h, 1 day, and 7 days post-SE) was not significantly different from controls whereas calbindin was found to decrease significantly throughout the hippocampus as early as 30 days after SE and remained decreased essentially for the life of the animals. This long-term decrease in calbindin expression may play a role in some of the long-term abnormalities observed in Ca 2+ homeostasis observed in this model of AE Raza et al, 2001;Raza et al, 2004;Delorenzo et al, 2005).…”

Section: Discussionmentioning

confidence: 73%

“…Calbindin buffering is one of several important mechanisms for neurons to maintain Ca 2+ homeostasis. It has been well established that hippocampal Ca 2+ homeostasis is disrupted following SE induced AE Raza et al, 2001;Raza et al, 2004;Delorenzo et al, 2005). This study was initiated to determine if hippocampal calbindin levels were altered following SE in association with epileptogenesis in this model of AE.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have demonstrated that SE produces acute and chronic elevations in intracellular Ca 2+ ([Ca 2+ ] i ) and alterations in Ca 2+ homeostatic mechanisms in the hippocampus, suggesting that alterations in Ca 2+ dynamics play a major role in the development of many of the neuronal plasticity changes associated with the induction of AE and the maintenance of the epileptic phenotype Raza et al, 2001;Raza et al, 2004;Delorenzo et al, 2005). Thus, it is important to understand the effects of epileptogenesis on Ca 2+ homeostatic mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…Altered Ca 2+ homeostasis is thought to underlie some aspects of the epileptic phenotype and contribute to the persistent neuroplasticity changes associated with acquired MTLE (Delorenzo et al, 2005). For instance, epileptic neurons in the pilocarpine model have been shown to maintain consistently higher baseline intracellular Ca 2+ levels in the range of 250 to 400 nM that peak up to high micromolar ranges (20-50 μM) after stimulation Raza et al, 2001). Moreover, these neurons show a delayed recovery of increased Ca 2+ homeostasis leading to abnormal baseline Ca 2+ levels in epileptic neurons.…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Otalora¹,

Hernandez²,

Arshadmansab³

et al. 2008

Brain Research

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In the hippocampus, BK channels are preferentially localized in presynaptic glutamatergic terminals including mossy fibers where they are thought to play an important role regulating excessive glutamate release during hyperactive states. Large conductance calcium-activated potassium channels (BK, MaxiK, Slo) have recently been implicated in the pathogenesis of genetic epilepsy. However, the role of BK channels in acquired mesial temporal lobe epilepsy (MTLE) remains unknown. Here we used immunohistochemistry, laser scanning confocal microscopy (LSCM), western immunoblotting and RT-PCR to investigate the expression pattern of the alpha-pore forming subunit of BK channels in the hippocampus and cortex of chronically epileptic rats obtained by the pilocarpine model of MTLE. All epileptic rats experiencing recurrent spontaneous seizures exhibited a significant down-regulation of BK channel immunostaining in the mossy fibers at the hilus and stratum lucidum of the CA3 area. Quantitative analysis of immunofluorescence signals by LSCM revealed a significant 47% reduction in BK channel in epileptic rats when compared to age-matched non-epileptic control rats. These data correlate with a similar reduction in BK channel protein levels and transcripts in the cortex and hippocampus. Our data indicate a seizure-related down-regulation of BK channels in chronically epileptic rats. Further functional assays are necessary to determine whether altered BK channel expression is an acquired channelopathy or a compensatory mechanism affecting the network excitability in MTLE. Moreover, seizure-mediated BK down-regulation may disturb neuronal excitability and presynaptic control at glutamatergic terminals triggering exaggerated glutamate release and seizures.

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“…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)(15)(16)(17)(18)(19).…”

Section: Immediately After Status Epilepticus (Se) Hippocampal Neuromentioning

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.

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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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Long-term alteration of calcium homeostatic mechanisms in the pilocarpine model of temporal lobe epilepsy

Cited by 93 publications

References 59 publications

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

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

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

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

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