Increased NMDA responses and dendritic degeneration in human epileptic hippocampal neurons in slices

Isokawa, Masako; Lévesque, Michel

doi:10.1016/0304-3940(91)90304-c

Cited by 169 publications

(71 citation statements)

References 18 publications

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“…Although the purpose of the present study was to investigate dynamic changes in lipid peroxidation and dendritic structures immediately after seizures, future studies over the longer period should be able to determine the long-term time course of these spine and dendritic changes. It is very likely that the spine loss seen in the present study is the initial phase of more chronic spine loss and progressive neurodegeneration reported in other studies (Muller et al, 1993;Multani et al, 1994;Isokawa and Levesque, 1991;Jiang et al, 1998;Zeng et al, 2007).…”

Section: Discusionsupporting

confidence: 54%

Pharmacologic suppression of oxidative damage and dendritic degeneration following kainic acid-induced excitotoxicity in mouse cerebrum

et al. 2008

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Intense seizure activity associated with status epilepticus and excitatory amino acid (EAA) imbalance initiates oxidative damage and neuronal injury in CA1 of the ventral hippocampus. We tested the hypothesis that dendritic degeneration of pyramidal neurons in the CA1 hippocampal area resulting from seizure-induced neurotoxicity is modulated by cerebral oxidative damage. Kainic acid (KA, 1 nmol/5 μl) was injected intracerebroventricularly to C57Bl/6 mice. F 2 -isoprostanes (F 2 -IsoPs) and F 4 -neuroprostanes (F 4 -NeuroPs) were used as surrogate measures of in vivo oxidative stress and biomarkers of lipid peroxidation. Nitric oxide synthase (NOS) activity was quantified by evaluating citrulline level and pyramidal neuron dendrites and spines were evaluated using rapid Golgi stains and a Neurolucida system. KA produced severe seizures in mice immediately after its administration and a significant (p<0.001) increase in F 2 -IsoPs, F 4 -NeuroPs and citrulline levels were seen 30 min following treatment. At the same time, hippocampal pyramidal neurons showed significant (p<0.001) reduction in dendritic length and spine density. In contrast, no significant change in neuronal dendrite and spine density or F 2 -IsoP, F 4 -NeuroPs and citrulline levels were found in mice pretreated with Vitamin E (α-tocopherol, 100 mg/kg, ip) for 3 days, or with N-tert-butyl-α-phenylnitrone (PBN, 200 mg/kg, ip) or ibuprofen (inhibitors of cyclooxygenase, COX, 14 μg/ml of drinking water) for 2 weeks prior to KA treatment. These findings indicate novel interactions among free radical-induced generation of F 2 -IsoPs and F 4 -NeuroPs, nitric oxide and dendritic degeneration, closely associate oxidative damage to neuronal membranes with degeneration of the dendritic system, and point to possible interventions to limit severe damage in acute neurological disorders.

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Section: Discusionsupporting

confidence: 54%

Pharmacologic suppression of oxidative damage and dendritic degeneration following kainic acid-induced excitotoxicity in mouse cerebrum

et al. 2008

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“…conventional fixed tissue analysis (Scheibel et al, 1974;Isokawa and Levesque, 1991;Muller et al, 1993;Multani et al, 1994;Drakew et al, 1996;Isokawa, 1998;Jiang et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…Dendritic spines represent the structural sites of contact for the majority of excitatory, glutamatergic synaptic inputs onto cortical neurons and are strongly implicated in mechanisms of synaptic plasticity and learning. A variety of studies demonstrate a loss of dendritic spines in pathological specimens from animal seizure models (Olney et al, 1983;Muller et al, 1993;Drakew et al, 1996;Isokawa, 1998;Jiang et al, 1998) or human epilepsy patients (Scheibel et al, 1974;Isokawa and Levesque, 1991;Multani et al, 1994), suggesting that seizures can cause dendritic injury. However, these previous studies using conventional histological analysis of fixed tissue are somewhat limited by the difficulty in distinguishing direct effects of seizures from potential confounding or coincidental factors and by the relatively slow time course of analysis, typically spanning hours to days.…”

Section: Introductionmentioning

confidence: 99%

Kainate Seizures Cause Acute Dendritic Injury and Actin DepolymerizationIn Vivo

Zeng¹,

Xu²,

Rensing³

et al. 2007

J. Neurosci.

149

134

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Seizures may cause brain injury via a variety of mechanisms, potentially contributing to cognitive deficits in epilepsy patients. Although seizures induce neuronal death in some situations, they may also have "nonlethal" pathophysiological effects on neuronal structure and function, such as modifying dendritic morphology. Previous studies involving conventional fixed tissue analysis have demonstrated a chronic loss of dendritic spines after seizures in animal models and human tissue. More recently, in vivo time-lapse imaging methods have been used to monitor acute changes in spines directly during seizures, but documented spine loss only under severe conditions. Here, we examined effects of secondary generalized seizures induced by kainate, on dendritic structure of neocortical neurons using multiphoton imaging in live mice in vivo and investigated molecular mechanisms mediating these structural changes. Higher-stage kainate-induced seizures caused dramatic dendritic beading and loss of spines within minutes, in the absence of neuronal death or changes in systemic oxygenation. Although the dendritic beading improved rapidly after the seizures, the spine loss recovered only partially over a 24 h period. Kainate seizures also resulted in activation of the actin-depolymerizing factor, cofilin, and a corresponding decrease in filamentous actin, indicating that depolymerization of actin may mediate the morphological dendritic changes. Finally, an inhibitor of the calcium-dependent phosphatase, calcineurin, antagonized the effects of seizures on cofilin activation and spine morphology. These dramatic in vivo findings demonstrate that seizures produce acute dendritic injury in neocortical neurons via calcineurindependent regulation of the actin cytoskeleton, suggesting novel therapeutic targets for preventing seizure-induced brain injury.

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“…Such pathological specimens obtained from or near the region of the epileptic focus in neocortex or hippocampus have revealed a number of abnormalities in dendrites, but most commonly demonstrate a loss of dendritic spines [50,51]. Dendritic spine loss is commonly seen in hippocampal pyramidal neurons and dentate granule cells in patients with temporal lobe epilepsy and may occur in isolation or associated with varicose swelling of the dendritic branches [52][53][54][55][56]. Similar findings of spine loss and dendritic swelling have also been documented in pyramidal neurons of neocortex, including sites distant from the primary epileptogenic focus [57].…”

Section: Dendritic Abnormalities In Epilepsymentioning

confidence: 99%

Stabilizing dendritic structure as a novel therapeutic approach for epilepsy

Wong¹

2008

Expert Review of Neurotherapeutics

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SummaryPeople with epilepsy often experience long-term cognitive dysfunction and other neurological deficits, including memory loss, learning disabilities, and neurobehavioral disorders, which may exhibit a progressive course correlating with worsening seizure control. Furthermore, one-third of epilepsy patients have seizures that are intractable to all available treatments. Thus, novel therapies for seizures and the neurological comorbidities of epilepsy are desperately needed. As most current treatments are merely "symptomatic" therapies that suppress seizures, recently epilepsy researchers have realized the critical need for novel therapeutic strategies targeting the underlying mechanisms of epileptogenesis and seizure-related brain injury. Yet to date, few such "anti-epileptogenic" therapies have emerged or are even in developmental stages. Although many seizure medications modulate the functional or physiological activity of neurons, a relatively unexplored therapeutic strategy for epilepsy are methods for stabilizing the structure of neurons. Human pathological studies and animal models of epilepsy demonstrate obvious structural abnormalities in dendrites of neurons, which could contribute to neuronal dysfunction, epileptogenesis, and cognitive/neurological deficits in epilepsy patients. This dendritic injury may be caused by activity-dependent breakdown of cytoskeletal elements, such as actin. Mechanistically-targeted approaches to limit seizure-related structural changes in dendrites may represent a novel therapeutic strategy for treating epilepsy and its complications.

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Increased NMDA responses and dendritic degeneration in human epileptic hippocampal neurons in slices

Cited by 169 publications

References 18 publications

Pharmacologic suppression of oxidative damage and dendritic degeneration following kainic acid-induced excitotoxicity in mouse cerebrum

Pharmacologic suppression of oxidative damage and dendritic degeneration following kainic acid-induced excitotoxicity in mouse cerebrum

Kainate Seizures Cause Acute Dendritic Injury and Actin DepolymerizationIn Vivo

Stabilizing dendritic structure as a novel therapeutic approach for epilepsy

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