Excitotoxicity induced by enhanced excitatory neurotransmission in cultured hippocampal pyramidal neurons

Abele, April E.; Scholz, Kenneth P.; Scholz, Wendy K.; Miller, Richard J.

doi:10.1016/0896-6273(90)90053-i

Cited by 149 publications

(101 citation statements)

References 31 publications

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“…Prolonged unopposed excitation kills neurons (Abele et al, 1990;Murray et al, 1998). Regardless of the precise mechanism, because Ad-1 -GFP transduction of hyperexcitable neurons decreases spontaneous activity, it may also decrease hyperexcitability-associated excitotoxic delayed neuronal death.…”

Section: Ad-1 -Gfp Transduction Suppresses Hyperexcitabilityinduced Dmentioning

confidence: 99%

Suppression of Neuronal Hyperexcitability and Associated Delayed Neuronal Death by Adenoviral Expression of GABA_CReceptors

2001

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The excessive neuronal excitation underlying several clinically important diseases is often treated with GABA allosteric modulators in an attempt to enhance inhibition. An alternative strategy would be to enhance directly the sensitivity of postsynaptic neurons to GABA. The GABA C receptor, normally found only in the retina, is more sensitive to GABA and demonstrates little desensitization compared with the GABA A receptor. We constructed an adenovirus vector that expressed cDNA for both the GABA C receptor 1 subunit and a green fluorescent protein (GFP) reporter and used it to transduce cultured hippocampal neurons. Transduced neurons were identified by fluorescence, double immunocytochemistry proved colocalization of the 1 protein and the reporter, Western blot verified the expected molecular masses, and electrophysiological and pharmacological properties confirmed the presence of functional GABA C receptors. 1 -GFP transduction resulted in an increased density of GABA A receptors as well as expression of novel GABA C receptors. This effect was not reproduced by addition of TTX or Mg 2ϩ to the culture medium to reduce action potentials or synaptic activity. In a model of neuronal hyperexcitability induced by chronic blockade of glutamate receptors, expression of GABA C receptors abolished the hyperactivity and the consequent delayed neuronal death. Adenovirus-mediated neuronal GABA C receptor engineering, via its dual mechanism of inhibition, may offer a way of inhibiting only those hyperexcitable neurons responsible for clinical problems, avoiding the generalized nervous system depression associated with pharmacological therapy.

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Section: Ad-1 -Gfp Transduction Suppresses Hyperexcitabilityinduced Dmentioning

confidence: 99%

Suppression of Neuronal Hyperexcitability and Associated Delayed Neuronal Death by Adenoviral Expression of GABA_CReceptors

2001

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“…Inhibition of NMDA receptors or calcium entry through NMDA receptors is neuroprotective in vitro [58][59][60] and in vivo [61,62].…”

Section: Neuronal Death and Calciummentioning

confidence: 99%

Pathophysiology of status epilepticus

Walker¹

2018

Neuroscience Letters

104

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Status epilepticus (SE) is the maximal expression of epilepsy with a high morbidity and mortality. It occurs due to the failure of mechanisms that terminate seizures.Both human and animal data indicate that the longer a seizure lasts, the less likely it is to stop. Recent evidence suggests that there is a critical transition from an ictal to a post-ictal state, associated with a transition from a spatio-temporally desynchronized state to a highly synchronized state, respectively.As SE continues, it becomes progressively resistant to drugs, in particular benzodiazepines due partly to NMDA receptor-dependent internalization of GABA (A) receptors. Moreover, excessive calcium entry into neurons through excessive NMDA receptor activation results in activation of nitric oxide synthase, calpains, and NADPH oxidase. The latter enzyme plays a critical part in the generation of seizuredependent reactive oxygen species. Calcium also accumulates in mitochondria resulting in mitochondrial failure (decreased ATP production), and opening of the mitochondrial permeability transition pore. Together these changes result in status epilepticus-dependent neuronal death via several pathways. Multiple downstream mechanisms including inflammation, break down of the blood-brain barrier, and changes in gene expression can contribute to later pathological processes including chronic epilepsy and cognitive decline.

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“…Cells were plated in DMEM containing 10% horse serum at a density of 5 ϫ 10 4 cells/cm 2 on 15 mm glass coverslips coated with polylisine (1 mg/ml). After 2-4 hr, coverslips were transferred to plates containing N2.1-defined media (2 ml) and a confluent bed of astroglia (Abele et al, 1990). AraC (10 M) was added to the cultures within 48 hr from plating.…”

Section: Hippocampal Neuronal Culturesmentioning

confidence: 99%

gp120-Induced Neurotoxicity in Hippocampal Pyramidal Neuron Cultures: Protective Action of TGF-β1

1996

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We found that TGF-␤1, a cytokine that previously has been reported to have neuroprotective effects, was able to prevent the toxicity induced by the HIV-1 coat protein gp120 in hippocampal pyramidal neuron cultures. In the presence of glia, gp120 induced time-and dose-dependent cell death, which was more pronounced in mature (7-19 d in culture) than in young neurons (2-7 d in culture). Staining with nuclear dyes (propidium iodide and Hoechst 33342), in situ detection of DNA fragments, and DNA analysis on agarose gels indicated that apoptosis was mainly responsible for the death caused by the viral protein. However, after several days of treatment, deathdisplaying necrotic features also occurred. Neurotoxicity induced by gp120 was dependent on the activation of NMDA receptors and required the presence of glia as well as new protein synthesis. Thus, the effect of gp120 was abolished by the NMDA receptor antagonist APV and partially reduced by cycloheximide. Only modest neurotoxicity was observed in pure neuronal cultures deprived of the glia feeder layer. Fura-2-based videoimaging showed that treatment with gp120 enhanced the ability of NMDA to increase neuronal [Ca 2ϩ ] i . The impairment of neuronal Ca 2ϩ homeostasis was prevented completely by TGF-␤1. Therefore, it is likely that the neuroprotective action of the cytokine is attributable to its ability to stabilize neuronal [Ca 2ϩ ] i .

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Excitotoxicity induced by enhanced excitatory neurotransmission in cultured hippocampal pyramidal neurons

Cited by 149 publications

References 31 publications

Suppression of Neuronal Hyperexcitability and Associated Delayed Neuronal Death by Adenoviral Expression of GABA_CReceptors

Suppression of Neuronal Hyperexcitability and Associated Delayed Neuronal Death by Adenoviral Expression of GABA_CReceptors

Pathophysiology of status epilepticus

gp120-Induced Neurotoxicity in Hippocampal Pyramidal Neuron Cultures: Protective Action of TGF-β1

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Excitotoxicity induced by enhanced excitatory neurotransmission in cultured hippocampal pyramidal neurons

Cited by 149 publications

References 31 publications

Suppression of Neuronal Hyperexcitability and Associated Delayed Neuronal Death by Adenoviral Expression of GABACReceptors

Suppression of Neuronal Hyperexcitability and Associated Delayed Neuronal Death by Adenoviral Expression of GABACReceptors

Pathophysiology of status epilepticus

gp120-Induced Neurotoxicity in Hippocampal Pyramidal Neuron Cultures: Protective Action of TGF-β1

Contact Info

Product

Resources

About

Suppression of Neuronal Hyperexcitability and Associated Delayed Neuronal Death by Adenoviral Expression of GABA_CReceptors

Suppression of Neuronal Hyperexcitability and Associated Delayed Neuronal Death by Adenoviral Expression of GABA_CReceptors