Reversible loss of dendritic spines and altered excitability after chronic epilepsy in hippocampal slice cultures.

Abstract

The morphological and functional consequences of epileptic activity were investigated by applying the convulsants bicuculline and/or picrotoxin to mature rat hippocampal slice cultures. After 3 days, some cells in all hippocampal subfields showed signs of degeneration, including swollen somata, vacuolation, and dendritic deformities, whereas others displayed only a massive reduction in the number of their dendritic spines. Intracellular recordings from CA3 pyramidal cells revealed a decrease in the amplitude of evoked excitatory synaptic potentials. y-Aminobutyric acid-releasing interneurons and inhibitory synaptic potentials were unaffected. Seven days after withdrawal of convulsants, remaining cells possessed a normal number of dendritic spines, thus demonstrating a considerable capacity for recovery. The pathological changes induced by convulsants are similar to those found in the hippocampi of human epileptics, suggesting that they are a consequence, rather than a cause, of epilepsy.Temporal lobe epilepsy and status epilepticus are associated with a characteristic pattern of cell damage in the hippocampus. There is usually a prominent loss of pyramidal and/or granule cells (1, 2). In addition, numerous deformities are observed in surviving neurons, including swollen and "beaded" dendrites, as well as a complete or partial loss of dendritic spines, as revealed in 4). Whether this neuropathology is the primary cause of the seizure disorder or rather a consequence of epileptic seizures resulting from some other etiology is not yet resolved. We have attempted to distinguish between these two possibilities by examining the effects of epileptic activity of known origin-namely, that induced by application of convulsant drugs-on neurons in hippocampal slice cultures maintained in vitro.

Stabilizing dendritic structure as a novel therapeutic approach for epilepsy

“…Similar to the clinical findings, a loss of dendritic spines and varicose swelling of dendrites is frequently found in histological sections obtained from rats that had acute seizures or chronic epilepsy induced in vivo by various methods, such as convulsant drugs or electrical kindling [60][61][62][63][64][65], although rarely an increase in dendrites or spines has been reported [66][67][68]. 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].…”

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

“…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).…”

Regulation of Dendritic Spine Density in Cultured Rat Hippocampal Neurons by Steroid Hormones

“…Thus, dendritic spines may prevent calcium surges from spreading into the parent dendrite and in that respect can be considered neuroprotectants (Harris and Kater, 1994;Segal, 1995b). Dendritic spines proliferate in the presence of excessive synaptic activity (Annis et al, 1994;Bundman et al, 1994;Papa and Segal, 1996), although some reports claim the opposite (Muller et al, 1993;Rocha and Sur, 1995). It is thought that most spines have one excitatory synapse on the head (Harris et al, 1992) and that most, if not all, excitatory synapses are on spines.…”