The pilocarpine model of temporal lobe epilepsy

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Abstract

Understanding the pathophysiogenesis of temporal lobe epilepsy (TLE) largely rests on the use of models of status epilepticus (SE), as in the case of the pilocarpine model. The main features of TLE are: (i) epileptic foci in the limbic system; (ii) an “initial precipitating injury”; (iii) the so-called “latent period”; and (iv) the presence of hippocampal sclerosis leading to reorganization of neuronal networks. Many of these characteristics can be reproduced in rodents by systemic injection of pilocarpine; in this animal model, SE is followed by a latent period and later by the appearance of spontaneous recurrent seizures (SRSs). These processes are, however, influenced by experimental conditions such as rodent species, strain, gender, age, doses and routes of pilocarpine administration, as well as combinations with other drugs administered before and/or after SE. In the attempt to limit these sources of variability, we evaluated the methodological procedures used by several investigators in the pilocarpine model; in particular, we have focused on the behavioural, electrophysiological and histopathological findings obtained with different protocols. We addressed the various experimental approaches published to date, by comparing mortality rates, onset of SRSs, neuronal damage, and network reorganization. Based on the evidence reviewed here, we propose that the pilocarpine model can be a valuable tool to investigate the mechanisms involved in TLE, and even more so when standardized to reduce mortality at the time of pilocarpine injection, differences in latent period duration, variability in the lesion extent, and SRS frequency.

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Cholinergic induction of network oscillations at 40 Hz in the hippocampus in vitro.

A Fisahn, F Pike, E Buhl … (1998)

Acetylcholine is vital for cognitive functions of the brain. Although its actions in the individual cell are known in some detail, its effects at the network level are poorly understood. The hippocampus, which receives a major cholinergic input from the medial septum/diagonal band, is important in memory and exhibits network activity at 40 Hz during relevant behaviours. Here we show that cholinergic activation is sufficient to induce 40-Hz network oscillations in the hippocampus in vitro. Oscillatory activity is generated spontaneously in the CA3 subfield and can persist for hours. During the oscillatory state, principal neurons fire action potentials that are phase-related to the extracellular oscillation, but each neuron fires in only a small proportion of the cycles. Both excitatory and inhibitory synaptic events participate during the network oscillation in a precise temporal pattern. These results indicate that subcortical cholinergic input can control hippocampal memory processing by inducing fast network oscillations.

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Kindling and status epilepticus models of epilepsy: rewiring the brain.

Kiyoshi Morimoto, Margaret Fahnestock, Ronald J Racine (2004)

This review focuses on the remodeling of brain circuitry associated with epilepsy, particularly in excitatory glutamate and inhibitory GABA systems, including alterations in synaptic efficacy, growth of new connections, and loss of existing connections. From recent studies on the kindling and status epilepticus models, which have been used most extensively to investigate temporal lobe epilepsy, it is now clear that the brain reorganizes itself in response to excess neural activation, such as seizure activity. The contributing factors to this reorganization include activation of glutamate receptors, second messengers, immediate early genes, transcription factors, neurotrophic factors, axon guidance molecules, protein synthesis, neurogenesis, and synaptogenesis. Some of the resulting changes may, in turn, contribute to the permanent alterations in seizure susceptibility. There is increasing evidence that neurogenesis and synaptogenesis can appear not only in the mossy fiber pathway in the hippocampus but also in other limbic structures. Neuronal loss, induced by prolonged seizure activity, may also contribute to circuit restructuring, particularly in the status epilepticus model. However, it is unlikely that any one structure, plastic system, neurotrophin, or downstream effector pathway is uniquely critical for epileptogenesis. The sensitivity of neural systems to the modulation of inhibition makes a disinhibition hypothesis compelling for both the triggering stage of the epileptic response and the long-term changes that promote the epileptic state. Loss of selective types of interneurons, alteration of GABA receptor configuration, and/or decrease in dendritic inhibition could contribute to the development of spontaneous seizures.

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Social regulation of the cortisol levels in early human development.

Megan Gunnar, Bonny Donzella (2015)

Other papers in this special edition provide evidence to implicate activity of the limbic hypothalamic-pituitary-adrenocortical (L-HPA) system in the etiology of drug and alcohol abuse. Furthermore, studies in rodents and primates suggest that responsivity and regulation of this system later in life may be shaped by social experiences during early development. Cortisol is the major hormonal product of the L-HPA system in humans. Although it provides only a partial understanding of the activity of this neuroendocrine axis, its regulation may bear importantly on human growth and development. We review developmental studies of cortisol and behavior in human children, birth to approximately 5 years of age. We describe the development of social buffering of cortisol responses that produces a functional analogue of the rodent stress hyporesponsive period by the time children are about 12 months of age. We further describe the sensitivity of cortisol activity to variations in care quality among infants and toddlers, along with evidence that children with negative emotional temperaments may be most likely to exhibit elevations in cortisol under conditions of less than optimal care. Finally, the few studies of cortisol activity under conditions of neglectful and abusive care of young children are considered, noting that these often have yielded evidence of reduced rather than increased cortisol levels.