Long-lasting decrease in neuronal Ca2+/calmodulin-dependent protein kinase II activity in a hippocampal neuronal culture model of spontaneous recurrent seizures

Blair, Robert E.; Churn, Severn B.; Sombati, Sompong; Lou, Jeffrey K.; DeLorenzo, Robert J.

doi:10.1016/s0006-8993(99)02100-9

Cited by 35 publications

(38 citation statements)

References 51 publications

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“…The serine residues within the ␤3 subunit are key residues for modulating GABA A R function (Brandon et al, , 2000, and dephosphorylation by CaN can decrease GABA A R-mediated responses to GABA (Chen and Wong, 1995), increase the rate of GABA unbinding (Jones and Westbrook, 1997), and decrease cell surface GABA A receptor stability (Connolly et al, 1999). The GABA A ␤2/3 protein also has been shown to undergo endocytosis after ictal activity in cultured hippocampal neurons, contributing to subsequent hyperexcitability (Blair et al, 1999). In this study, we showed that hypoxiainduced seizures resulted in decreased GABA A R phosphorylation concomitant with a decrease in IPSC amplitudes, and furthermore, the decrease in IPSC amplitudes could be partially reversed by CaN inhibition.…”

Section: Endogenous Can Activation Regulates Gaba a R Synaptic Inhibisupporting

confidence: 48%

AMPA/Kainate Receptor-Mediated Downregulation of GABAergic Synaptic Transmission by Calcineurin after Seizures in the Developing Rat Brain

Sánchez¹,

Dai²,

Levada³

et al. 2005

J. Neurosci.

103

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Section: Endogenous Can Activation Regulates Gaba a R Synaptic Inhibisupporting

confidence: 48%

AMPA/Kainate Receptor-Mediated Downregulation of GABAergic Synaptic Transmission by Calcineurin after Seizures in the Developing Rat Brain

Sánchez¹,

Dai²,

Levada³

et al. 2005

J. Neurosci.

103

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“…For example, decreased CaMKII activity and α subunit expression are observed in the low-Mg 2+ hippocampal neuronal culture model (Blair et al, 1999). Like epileptogenesis, these changes are dependent on NMDA receptor activation (Blair et al, 1999;Kochan et al, 2000).Decreased CaMKII activity has been further implicated in epileptogenesis by experiments using transgenic mice with a null mutation for the α subunit of CaMKII. These mice, lacking active CaMKII, manifest epileptiform activity after subconvulsive stimulation (Butler et al, 1995).…”

Section: Effects Of Altered [Ca 2+ ] I On Ca 2+ -Regulated Enzyme Sysmentioning

confidence: 99%

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

DeLorenzo

Sun

Deshpande

2005

Pharmacology & Therapeutics

258

286

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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-calmodulin-dependent protein kinase II (CaMK-II) plays a major role in modulating neuronal excitability and function (Kelly et al, 1984), with alterations in CaMK-II levels linked to neuronal hyperexcitability. Decreases in CaM kinase II have been reported in numerous in vivo and in vitro models of epilepsy (Bronstein et al, 1993), including kindling (Wasterlain and Farber, 1984;Taft et al, 1987), electrical stimulation SE (Perlin et al, 1992), pilocarpine (Churn et al, 2000a), and low Mg 2ϩ in cultured neurons (Blair et al, 1999). Furthermore, CaMK-II knockout mice demonstrated the epileptic phenotype and developed spontaneous seizures (Butler et al, 1995).…”

mentioning

confidence: 99%

“…It has been demonstrated that knocking down CaMK-II activity in cultured hippocampal neurons with an antisense oligonucleotide resulted in epileptiform activity as evidenced by the presence of SREDs (Churn et al, 2000b). It was also shown in cultured hippocampal neurons that CaMK-II activity was decreased in association with the development of SREDs (Blair et al, 1999). These studies implicate a role for altered CaMK-II function toward the induction and maintenance of the epileptic phenotype and suggest that alterations in CaMK-II activity may play a role in the induction of epileptogenesis by altering Ca 2ϩ homeostatic mechanisms.…”

mentioning

confidence: 99%

Altered Calcium/Calmodulin Kinase II Activity Changes Calcium Homeostasis That Underlies Epileptiform Activity in Hippocampal Neurons in Culture

Carter

Haider

Blair

et al. 2006

J Pharmacol Exp Ther

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Epilepsy is characterized by the occurrence of spontaneous recurrent epileptiform discharges (SREDs) in neurons. A decrease in calcium/calmodulin-dependent protein kinase II (CaMK-II) activity has been shown to occur with the development of SREDs in a hippocampal neuronal culture model of acquired epilepsy, and altered calcium (Ca 2ϩ ) homeostasis has been implicated in the development of SREDs. Using antisense oligonucleotides, this study was conducted to determine whether selective suppression of CaMK-II activity, with subsequent induction of SREDs, was associated with altered Ca 2ϩ homeostasis in hippocampal neurons in culture. Antisense knockdown resulted in the development of SREDs and a decrease in both immunocytochemical staining and enzyme activity of CaMK-II. Evaluation of [Ca 2ϩ ] i using Fura indicators revealed that antisense-treated neurons manifested increased basal [Ca 2ϩ ] i , whereas missense-treated neurons showed no change in basal [Ca 2ϩ ] i . Antisense suppression of CaMK-II was also associated with an inability of neurons to restore a Ca 2ϩ load. Upon removal of oligonucleotide treatment, CaMK-II suppression and Ca 2ϩ homeostasis recovered to control levels and SREDs were abolished. To our knowledge, the results demonstrate the first evidence that selective suppression of CaMK-II activity results in alterations in Ca 2ϩ homeostasis and the development of SREDs in hippocampal neurons and suggest that CaMK-II suppression may be causing epileptogenesis by altering Ca 2ϩ homeostatic mechanisms.

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Long-lasting decrease in neuronal Ca2+/calmodulin-dependent protein kinase II activity in a hippocampal neuronal culture model of spontaneous recurrent seizures

Cited by 35 publications

References 51 publications

AMPA/Kainate Receptor-Mediated Downregulation of GABAergic Synaptic Transmission by Calcineurin after Seizures in the Developing Rat Brain

AMPA/Kainate Receptor-Mediated Downregulation of GABAergic Synaptic Transmission by Calcineurin after Seizures in the Developing Rat Brain

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

Altered Calcium/Calmodulin Kinase II Activity Changes Calcium Homeostasis That Underlies Epileptiform Activity in Hippocampal Neurons in Culture

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