Kainate Seizures Cause Acute Dendritic Injury and Actin DepolymerizationIn Vivo

Abstract

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.

Conditional deletion of the NMDA-NR1 receptor subunit gene in the central nucleus of the amygdala inhibits naloxone-induced conditioned place aversion in morphine-dependent mice

“…Ultrastructural morphological analysis demonstrated that there were no signs of swelling or condensation in neuronal somata or nuclei, as shown by a number of parameters including the nuclear form factor, a widely used measure of nuclear pathology (Chan et al, 2000). Dendritic spine morphology has also been shown to be associated with neural toxicity, which may involve NMDA receptor activation (Ackermann and Matus, 2003;Gisselsson et al, 2005;Zeng et al, 2007). Ultrastructural morphometric analysis showed no differences in spine cross-sectional or surface areas in rAAV-GFP-Cre administered hemispheres, indicating that NR1 deletion was not associated with changes in basal dendritic spine integrity.…”

Stabilizing dendritic structure as a novel therapeutic approach for epilepsy

“…Furthermore, spine loss and other dendritic changes can also occur with in vitro seizure models involving epileptiform bursting in brain slice-cultures [69][70][71][72]. While previous studies have utilized fixed-tissue methods to give isolated, static views of dendritic injury, recently modern microscopy methods have directly visualized seizure-related dendritic injury with time-lapse imaging in living animals in vivo [73][74][75]. These in vivo time-lapse studies have demonstrated a remarkable evolution of dendritic injury acutely following seizures, first with a transient beading of dendrites that resolves quickly within a couple hours after a seizure, followed by a more persistent loss of dendritic spines (Fig.…”

“…Recent evidence suggests that specific calcium-activated enzymes, such as calcineurin, are activated in animal models of epilepsy [86]. Furthermore, actin and actin-associated proteins are regulated by acute seizures or during chronic epileptogenesis [75,87,88]. In particular, seizures lead to acute depolymerization of filamentous actin, which could directly account for structural changes in dendrites [75].…”

“…Furthermore, actin and actin-associated proteins are regulated by acute seizures or during chronic epileptogenesis [75,87,88]. In particular, seizures lead to acute depolymerization of filamentous actin, which could directly account for structural changes in dendrites [75]. Thus, a logical mechanistic scheme mediating dendritic injury in epilepsy could involve dysregulation of intracellular calcium within spines, activation of a cascade of calcium-dependent phosphatases and kinases, and depolymerization of F-actin, with resultant breakdown of the actin cytoskeleton of dendrites (Fig.…”

Matrix Metalloproteinase-9 Contributes to Kindled Seizure Development in Pentylenetetrazole-Treated Mice by Converting Pro-BDNF to Mature BDNF in the Hippocampus

“…Although seizures induce neuronal death in some situations, they also can produce nonlethal pathophysiologic effects on neuronal structures and functions (Zeng et al, 2007). Kindling is an experimental epilepsy model in which repeated electrical or chemical stimulation of certain forebrain structures triggers progressively more intense electroencephalographic and behavioral seizure activity (Goddard et al, 1969;Racine, 1972).…”