Spine loss and other dendritic abnormalities in epilepsy

Abstract

Studies of neurons from human epilepsy tissue and comparable animal models of focal epilepsy have consistently reported a marked decrease in dendritic spine density on hippocampal and neocortical pyramidal cells. Spine loss is often accompanied by focal varicose swellings or beading of dendritic segments. An ongoing excitotoxic injury of dendrites (dendrotoxicity), produced by excessive release of glutamate during seizures, is often assumed to produce these abnormalities. Indeed, application of glutamate receptor agonists to dendrites can produce both spine loss and beading. However, the cellular mechanisms underlying the two processes appear to be different. One recent study suggests NMDA‐induced spine loss is produced by Ca2+‐mediated alterations of the spine cytoskeleton. In contrast, dendritic beading is not dependent on extracellular Ca2+; instead, it appears to be produced by the movement of Na+ and Cl− intracellularly and an obligate movement of water to maintain osmolarity. A decrease in dendritic spine density was recently reported in a model of recurrent focal seizures in early life. Unlike results from other models, dendritic beading was not observed, and other signs of neuronal injury and death were absent. Thus, additional mechanisms to those of excitotoxicity may produce dendritic spine loss in epileptic tissue. A hypothesis is presented that spine loss can be a product of a partial deafferentation of pyramidal cells, resulting from an activity‐dependent pruning of neuronal connectivity induced by recurring seizures. The dendritic abnormalities observed in epilepsy are commonly suggested to be a product and not a cause of epilepsy. However, anatomical remodeling may be accompanied by alterations in molecular expression and targeting of both voltage‐ and ligand‐gated channels in dendrites. It is conceivable that such changes could contribute to the neuronal hyperexcitability of epilepsy. Hippocampus 2000;10:617–625. © 2000 Wiley‐Liss, Inc.

Neuritic Beading Induced by Activated Microglia Is an Early Feature of Neuronal Dysfunction Toward Neuronal Death by Inhibition of Mitochondrial Respiration and Axonal Transport

“…Neuritic beading is observed in various pathological conditions (23)(24)(25)(26)(27)(28)(29)(30)(31). Our current results indicate that neuritic beads represent the accumulation of vesicular cargo and transport proteins following damage to the transport mechanisms by activated microglia.…”

“…Focal bead-like swelling in dendrites and axons (neuritic beading) is thought to be a neuropathological sign in ischemia (23), epilepsy (24), mechanical pressure (25), brain tumor (26), aging (27), and neurodegenerative diseases such as Alzheimer disease (28), Parkinson disease (29), and amyotrophic lateral sclerosis (30,31). Neuritic beading is also induced by various stimuli such as glutamate, nitric oxide (NO), 1 hypoxia, oxidative stress, glucose starvation, and hypotonic conditions (32)(33)(34)(35)(36)(37)(38).…”

Rapid regulation of microtubule-associated protein 2 in dendrites of nucleus laminaris of the chick following deprivation of afferent activity

“…Among a number of regulatory mechanisms controlling MAP2 function (see review, Sánchez et al, 2000), changes in calcium signaling, especially rises in intracellular calcium concentration ([Ca 2+ ] i ), have been most extensively studied following manipulations of synaptic inputs. Excessive glutamate receptor stimulation induced by physiological stimulation or exposure of glutamate or agonists of its receptors causes dendritic injury and/or MAP2 loss (Siman and Noszek, 1988;Bigot et al, 1991;Felipo et al, 1993;Arias et al, 1997;Faddis et al, 1997;Steward and Halpain, 1999;Swann et al, 2000;Vaillant et al, 2002). Recent studies in hippocampal slices further demonstrated that these changes are calcium-dependent (Hoskison and Shuttleworth, 2006;Hoskison et al, 2007).…”

Loss of Astrocytic Domain Organization in the Epileptic Brain

“…Histological and retrograde tracer techniques have shown that kainate-induced epilepsy is associated with a dendritic sprouting of mossy fibers and new synapse formation in the dentate gyrus (Tauck and Nadler, 1985;Ben-Ari and Cossart, 2000;Wuarin and Dudek, 2001). However, the number of dendritic spines is reduced in other experimental seizure models (Swann et al, 2000), suggesting that epilepsy also can be linked to a partial deafferentation of cortical neurons.…”