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Serotonin is implicated in the regulation of seizures, but whether or not it can potentiate the effects of epileptogenic factors is not fully established. Using the kainic acid model of epilepsy in rats, we tested the effects of serotonin depletion on (1) susceptibility to acute seizures, (2) development of spontaneous recurrent seizures and (3) behavioral and neuroanatomical sequelae of kainic acid treatment. Serotonin was depleted by pretreating rats with p-chlorophenylalanine. In different groups, kainic acid was injected at 3 different doses: 6.5mg/kg, 9.0mg/kg or 12.5mg/kg. A single dose of 6.5mg/kg of kainic acid reliably induced status epilepticus in p-chlorophenylalanine-pretreated rats, but not in saline-pretreated rats. The neuroexcitatory effects of kainic acid in the p-chlorophenylalanine-pretreated rats, but not in saline-pretreated rats, were associated with the presence of tonic-clonic convulsions and high lethality. Compared to controls, a greater portion of serotonin-depleted rats showed spontaneous recurrent seizures after kainic acid injections. Loss of hippocampal neurons and spatial memory deficits associated with kainic acid treatment were exacerbated by prior depletion of serotonin. The present findings are of particular importance because they suggest that low serotonin activity may represent one of the major risk factors for epilepsy and, thus, offer potentially relevant targets for prevention of epileptogenesis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The septohippocampal cholinergic neurotransmission has long been implicated in seizures, but little is known about the structural features of this projection system in epileptic brain. We evaluated the effects of experimental epilepsy on the areal density of cholinergic terminals (fiber varicosities) in the dentate gyrus. For this purpose, we used two distinct post-status epilepticus rat models, in which epilepsy was induced with injections of either kainic acid or pilocarpine. To visualize the cholinergic fibers, we used brain sections immunostained for the vesicular acetylcholine transporter. It was found that the density of cholinergic fiber varicosities was higher in epileptic rats versus control rats in the inner and outer zones of the dentate molecular layer, but it was reduced in the dentate hilus. We further evaluated the effects of kainate treatment on the total number, density, and soma volume of septal cholinergic cells, which were visualized in brain sections stained for either vesicular acetylcholine transporter or choline acetyltransferase (ChAT). Both the number of septal cells with cholinergic phenotype and their density were increased in epileptic rats when compared to control rats. The septal cells stained for vesicular acetylcholine transporter, but not for ChAT, have enlarged perikarya in epileptic rats. These results revealed previously unknown details of structural reorganization of the septohippocampal cholinergic system in experimental epilepsy, involving fiber sprouting into the dentate molecular layer and a parallel fiber retraction from the dentate hilus. We hypothesize that epilepsy-related neuroplasticity of septohippocampal cholinergic neurons is capable of increasing neuronal excitability of the dentate gyrus., (© 2017 Wiley Periodicals, Inc.)

Treating rats with kainic acid induces status epilepticus (SE) and leads to the development of behavioral deficits and spontaneous recurrent seizures later in life. However, in a subset of rats, kainic acid treatment does not induce overt behaviorally obvious acute SE. The goal of this study was to compare the neuroanatomical and behavioral changes induced by kainate in rats that developed convulsive SE to those who did not. Adult male Wistar rats were treated with kainic acid and tested behaviorally 5 months later. Rats that had experienced convulsive SE showed impaired performance on the spatial water maze and passive avoidance tasks, and on the context and tone retention tests following fear conditioning. In addition, they exhibited less anxiety-like behaviors than controls on the open-field and elevated plus-maze tests. Histologically, convulsive SE was associated with marked neuron loss in the hippocampal CA3 and CA1 fields, and in the dentate hilus. Rats that had not experienced convulsive SE after kainate treatment showed less severe, but significant impairments on the spatial water maze and passive avoidance tasks. These rats had fewer neurons than control rats in the dentate hilus, but not in the hippocampal CA3 and CA1 fields. Correlational analyses revealed significant relationships between spatial memory indices of rats and neuronal numbers in the dentate hilus and CA3 pyramidal field. These results show that a part of the animals that do not display intense behavioral seizures (convulsive SE) immediately after an epileptogenic treatment, later in life, they may still have noticeable structural and functional changes in the brain.

Prolonged seizures produce death of hippocampal neurons, which is thought to initiate epileptogenesis and cause a disruption of hippocampally mediated behaviors. This study aimed to evaluate behavioral and neuroanatomical changes induced by brief seizures and to compare them with changes induced by prolonged seizures. Adult rats were administered 6 brief seizures, elicited by electroshock (ECS). Prolonged seizures (status epilepticus, SE) were induced by pilocarpine. Two months later, the rats' behavior was tested using the Morris water maze, passive avoidance and active avoidance tests. The number of neurons in the hippocampal formation was estimated using stereological methods. ECS seizures produced loss of neurons, ranging between 14% and 26%, in the dentate hilus, subiculum, presubiculum, parasubiculum, and entorhinal layers III and V/VI. However, the neuron loss caused by SE in the same structures, as well as in the hippocampal CA3 and CA1 fields, ranged between 34% and 50%. SE additionally killed many neurons in the dentate granular layer, postsubiculum and entorhinal layer II. ECS treatment caused mild impairments in spatial learning and passive avoidance, but it was not associated with spontaneous motor seizures. In contrast, SE produced a severe disruption of spatial learning, passive and active avoidance, and led to the development of spontaneous seizures. These data show that both prolonged seizure activity and brief seizures result in structural and functional alterations in the temporal lobe circuits, but those caused by prolonged seizures are considerably more severe. Hippocampal damage elicited by brief seizures does not necessarily lead to spontaneous motor seizures., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The hippocampal formation undergoes considerable structural and functional modifications during aging and oxidative stress emerges as a key player in the process. In the present study, we investigated whether prolonged consumption of green tea (GT), which contains large amounts of polyphenols, could interfere with age-related changes in this brain region using biochemical, morphological and behavioral approaches. Ten male Wistar rats aged 19 months were fed with GT since 12 months of age and results compared to those obtained from controls aged 19 months (C-19M). At 12 months of age, another group of rats was evaluated to provide baseline data. Oxidative stress markers (protein carbonyls and malondialdehyde) were quantified in hippocampal homogenates and stereological methods were applied to estimate the deposition of lipofuscin in hippocampal CA3 pyramidal neurons. Morris water maze was used to assess spatial learning and memory. Aging increased oxidative markers and lipofuscin accumulation and was associated with impaired memory acquisition. However, GT treatment protected proteins and lipids against oxidation and prevented the increase of lipofuscin deposition compared to age-matched controls. Furthermore, the spatial learning abilities of GT-treated rats were significantly improved when compared to those from C-19M group. Taken together, these findings confirm the neuroprotective ability of GT in the hippocampal formation probably due to the reduction of oxidative stress-related damage observed during aging., (Copyright © 2009 Elsevier Inc. All rights reserved.)

The cholinergic septohippocampal pathway has long been known to be important for learning and memory. Prolonged intake of ethanol causes enduring memory deficits, which are paralleled by partial depletion of hippocampal cholinergic afferents. We hypothesized that exogenous supply of nerve growth factor (NGF), known to serve as a trophic substance for septal cholinergic neurons, can revert the ethanol-induced changes in the septohippocampal cholinergic system. Adult rats were given a 20% ethanol solution as their only source of fluid for 6 months. During the first 4 weeks after the animals were withdrawn from ethanol, they were intraventricularly infused with either NGF or vehicle alone via implanted osmotic minipumps. The vehicle-infused withdrawn animals showed impaired performance on a spatial reference memory version of the Morris water maze task, both during the task acquisition and on the retention test. In contrast, NGF-treated withdrawn rats were able to learn the task as well as controls, and significantly outperformed the vehicle-infused withdrawn rats. The histological analysis revealed that, in the latter group, the length density of fibers immunoreactive to choline acetyltransferase was reduced relative to control values by approximately 25%, as measured in the dentate gyrus and regio superior of the hippocampal formation. However, in NGF-treated withdrawn rats, the length density of these fibers was identical to that of control rats. These data provide support to the notion that NGF is capable of ameliorating memory deficits and restoring septohippocampal cholinergic projections following chronic treatment with ethanol.

The hippocampal formation undergoes significant morphological and functional changes after prolonged feeding with low-protein diets. In this study we tested whether prolonged food restriction causes deleterious alterations in this brain region as well. It was found that the total number of dentate granule cells and hippocampal CA3 and CA1 pyramidal neurons did not differ between controls and rats submitted to food restriction (40%) for 36 weeks. Likewise, no effects of this dietary regimen have been detected on the morphology of the dendritic trees of hippocampal pyramids, and on the total number of the mossy fiber-CA3 synapses. By contrast, the dendritic arborizations of granule cells were found to have a reduced number of segments in food-restricted rats. However, the spine density on the distal segments of their dendritic trees and the total number of axospinous synapses in the outer molecular layer of the dentate gyrus were increased in these animals. In addition, the total dendritic length of the granule cells and the overall surface area of the active zones of the synapses in the outer molecular layer were preserved, indicating that the capacity of dentate granule cells to process afferent stimuli is likely to be unaffected by this dietary treatment. Supporting this view are the results obtained in the water maze experiment which show that food-restricted rats exhibit unimpaired spatial abilities, which are known to be dependent on the entorhinal drive towards the hippocampal formation. These results show that, among hippocampal neurons, dentate granule cells are selectively vulnerable to food restriction. Nonetheless, the reorganization which takes place in their dendrites and synapses is capable of minimizing the functional impairments that were expected to occur following changes in the hippocampal neuronal circuitry induced by this type of dietary restriction.