Excitotoxicity induced by kainic acid provokes glycogen synthase kinase-3 truncation in the hippocampus

Jurado‐Arjona, Jerónimo; Goñi-Oliver, Paloma; Rodríguez-Prada, Lucía; Engel, Tobías; Henshall, David C.; Ávila, Jesús; Hernández, Félix

doi:10.1016/j.brainres.2015.03.016

Cited by 3 publications

(4 citation statements)

References 31 publications

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“…GSK-3β has been shown to be truncated by calpains at the N-terminal end removing the inhibitory Ser9 phosphorylation side, thereby increasing GSK-3β activity 34 . Notably, we previously showed in the intra-amygdala KA mouse model that this was most evident in the CA3 subfield 35 , possibly contributing to seizure-induced neurodegeneration. GSK-3β truncation in CA3 may also be the reason why this specific subfield showed no increase in GSK-3β Ser9 phosphorylation.…”

Section: Discussionmentioning

confidence: 89%

“…Studies of GSK-3β activity indicate that seizures may promote inhibition via Ser9 phosphorylation 8 , 10 , 12 , 26 , 33 . Conversely, seizures have been reported to result in calpain-mediated truncation of GSK-3, which is predicted to increase GSK-3 activation 34 , 35 . GSK-3 has also been linked to mossy fiber sprouting 25 , 26 .…”

Section: Introductionmentioning

confidence: 99%

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Bi-directional genetic modulation of GSK-3β exacerbates hippocampal neuropathology in experimental status epilepticus

et al. 2018

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Glycogen synthase kinase-3 (GSK-3) is ubiquitously expressed throughout the brain and involved in vital molecular pathways such as cell survival and synaptic reorganization and has emerged as a potential drug target for brain diseases. A causal role for GSK-3, in particular the brain-enriched GSK-3β isoform, has been demonstrated in neurodegenerative diseases such as Alzheimer’s and Huntington’s, and in psychiatric diseases. Recent studies have also linked GSK-3 dysregulation to neuropathological outcomes in epilepsy. To date, however, there has been no genetic evidence for the involvement of GSK-3 in seizure-induced pathology. Status epilepticus (prolonged, damaging seizure) was induced via a microinjection of kainic acid into the amygdala of mice. Studies were conducted using two transgenic mouse lines: a neuron-specific GSK-3β overexpression and a neuron-specific dominant-negative GSK-3β (GSK-3β-DN) expression in order to determine the effects of increased or decreased GSK-3β activity, respectively, on seizures and attendant pathological changes in the hippocampus. GSK-3 inhibitors were also employed to support the genetic approach. Status epilepticus resulted in a spatiotemporal regulation of GSK-3 expression and activity in the hippocampus, with decreased GSK-3 activity evident in non-damaged hippocampal areas. Consistent with this, overexpression of GSK-3β exacerbated status epilepticus-induced neurodegeneration in mice. Surprisingly, decreasing GSK-3 activity, either via overexpression of GSK-3β-DN or through the use of specific GSK-3 inhibitors, also exacerbated hippocampal damage and increased seizure severity during status epilepticus. In conclusion, our results demonstrate that the brain has limited tolerance for modulation of GSK-3 activity in the setting of epileptic brain injury. These findings caution against targeting GSK-3 as a treatment strategy for epilepsy or other neurologic disorders where neuronal hyperexcitability is an underlying pathomechanism.

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Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Bi-directional genetic modulation of GSK-3β exacerbates hippocampal neuropathology in experimental status epilepticus

et al. 2018

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“…The calpain inhibitor calpeptin (Santa Cruz, Dallas, Texas, USA; 10 μM) [103] was added to the OHCs’ serum-free medium followed immediately by a sham- or blast-injury. After the injury, samples were transferred to fresh serum-free medium containing the same concentration of calpeptin and PI (EMD Millipore; 2 μM).…”

Section: Methodsmentioning

confidence: 99%

Acute death of astrocytes in blast-exposed rat organotypic hippocampal slice cultures

et al. 2017

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Blast traumatic brain injury (bTBI) affects civilians, soldiers, and veterans worldwide and presents significant health concerns. The mechanisms of neurodegeneration following bTBI remain elusive and current therapies are largely ineffective. It is important to better characterize blast-evoked cellular changes and underlying mechanisms in order to develop more effective therapies. In the present study, our group utilized rat organotypic hippocampal slice cultures (OHCs) as an in vitro system to model bTBI. OHCs were exposed to either 138 ± 22 kPa (low) or 273 ± 23 kPa (high) overpressures using an open-ended helium-driven shock tube, or were assigned to sham control group. At 2 hours (h) following injury, we have characterized the astrocytic response to a blast overpressure. Immunostaining against the astrocytic marker glial fibrillary acidic protein (GFAP) revealed acute shearing and morphological changes in astrocytes, including clasmatodendrosis. Moreover, overlap of GFAP immunostaining and propidium iodide (PI) indicated astrocytic death. Quantification of the number of dead astrocytes per counting area in the hippocampal cornu Ammonis 1 region (CA1), demonstrated a significant increase in dead astrocytes in the low- and high-blast, compared to sham control OHCs. However only a small number of GFAP-expressing astrocytes were co-labeled with the apoptotic marker Annexin V, suggesting necrosis as the primary type of cell death in the acute phase following blast exposure. Moreover, western blot analyses revealed calpain mediated breakdown of GFAP. The dextran exclusion additionally indicated membrane disruption as a potential mechanism of acute astrocytic death. Furthermore, although blast exposure did not evoke significant changes in glutamate transporter 1 (GLT-1) expression, loss of GLT-1-expressing astrocytes suggests dysregulation of glutamate uptake following injury. Our data illustrate the profound effect of blast overpressure on astrocytes in OHCs at 2 h following injury and suggest increased calpain activity and membrane disruption as potential underlying mechanisms.

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“…Organotypic slice cultures of the hippocampus were prepared from 5-month-old wt or ASMko mice, as previously described ( 30 ). Six slices (400 m thick each) were placed per insert and cultured for 24 h at 37°C in a 5% CO 2 atmosphere prior to infection.…”

Section: Hippocampal Slice Culturesmentioning

confidence: 99%

Host sphingomyelin increases West Nile virus infection in vivo

Martín-Acebes

Gabandé‐Rodríguez

García-Cabrero

et al. 2016

Journal of Lipid Research

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The fl avivirus, West Nile virus (WNV), is a neurotropic enveloped plus-strand RNA virus transmitted through the bite of mosquitoes. This virus is responsible for recurrent outbreaks of febrile illness and meningoencephalitis worldwide, accounting for hundreds of human deaths every year ( 2 ). The WNV lifecycle is intimately associated to cellular lipids, and RNA replication and virion biogenesis are coupled into highly remodeled intracellular membranes ( 3, 4 ). In a parallel manner to that described for other fl aviviruses, both RNA replication and acquisition of lipid envelope are associated to specialized membranous structures derived from the endoplasmic reticulum (ER) ( 3-6 ). To generate this adequate environment for viral multiplication, WNV promotes the synthesis and accumulation of specifi c lipids (fatty acids, cholesterol, glycerophospholipids, and sphingolipids) within infected cells ( 5,(7)(8)(9). This selective manipulation of host cell lipid metabolism is not a unique feature of WNV infection, as it is also observed in cells infected with other fl aviviruses ( 10-12 ).Among the cellular lipids co-opted by WNV, sphingolipids merit special attention because they are particularly enriched in the nervous system, a major target tissue during WNV infection ( 13,14 ). Sphingolipids derive from sphingosine, a long-chain amino alcohol that is acylated with a long-chain fatty acid to give ceramide, which

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Excitotoxicity induced by kainic acid provokes glycogen synthase kinase-3 truncation in the hippocampus

Cited by 3 publications

References 31 publications

Bi-directional genetic modulation of GSK-3β exacerbates hippocampal neuropathology in experimental status epilepticus

Bi-directional genetic modulation of GSK-3β exacerbates hippocampal neuropathology in experimental status epilepticus

Acute death of astrocytes in blast-exposed rat organotypic hippocampal slice cultures

Host sphingomyelin increases West Nile virus infection in vivo

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