Postnatal inflammation increases seizure susceptibility in adult rats.

There are critical postnatal periods during which even subtle interventions can have long-lasting effects on adult physiology. We asked whether an immune challenge during early postnatal development can alter neuronal excitability and seizure susceptibility in adults. Postnatal day 14 (P14) male Sprague Dawley rats were injected with the bacterial endotoxin lipopolysaccharide (LPS), and control animals received sterile saline. Three weeks later, extracellular recordings from hippocampal slices revealed enhanced field EPSP slopes after Schaffer collateral stimulation and increased epileptiform burst-firing activity in CA1 after 4-aminopyridine application. Six to 8 weeks after postnatal LPS injection, seizure susceptibility was assessed in response to lithium-pilocarpine, kainic acid, and pentylenetetrazol. Rats treated with LPS showed significantly greater adult seizure susceptibility to all convulsants, as well as increased cytokine release and enhanced neuronal degeneration within the hippocampus after limbic seizures. These persistent increases in seizure susceptibility occurred only when LPS was given during a critical postnatal period (P7 and P14) and not before (P1) or after (P20). This early effect of LPS on adult seizures was blocked by concurrent intracerebroventricular administration of a tumor necrosis factor alpha (TNFalpha) antibody and mimicked by intracerebroventricular injection of rat recombinant TNFalpha. Postnatal LPS injection did not result in permanent changes in microglial (Iba1) activity or hippocampal cytokine [IL-1beta (interleukin-1beta) and TNFalpha] levels, but caused a slight increase in astrocyte (GFAP) numbers. These novel results indicate that a single LPS injection during a critical postnatal period causes a long-lasting increase in seizure susceptibility that is strongly dependent on TNFalpha.

Blockade of androgen receptors is sufficient to alter the sexual differentiation of the substantia nigra pars reticulata seizure-controlling network.

The substantia nigra pars reticulata (SNR) controls seizures in a sex-specific manner. At postnatal day 15 (P15), SNR infusion of GABA(A) receptor agonist muscimol have proconvulsant effects in males but not in females. In males, administration of an androgen receptor antagonist flutamide between P0-P2 led to the disappearance of the proconvulsant muscimol effects at P15. Thus, activation of androgen receptors is important for the presence of proconvulsant SNR muscimol responses.

Early life immune challenge--effects on behavioural indices of adult rat fear and anxiety.

Neonatal exposure to an immune challenge has been shown to alter many facets of adult physiology including fever responses to a similar infection. However, there is a paucity of information regarding its effects on adult behaviours. Male Sprague-Dawley rats were administered a single injection of the bacterial endotoxin lipopolysaccharide (LPS) at 14 days old and were compared, when they reached adulthood, with neonatally saline-treated controls in several behavioural tests of unconditioned fear and anxiety. There was no effect of the neonatal treatment on performance in either the elevated plus maze, modified Porsolt's forced swim test or the open field test. However, neonatally LPS-treated rats did show significantly reduced exploration of novel objects introduced to the open field arena, indicating an effect of the neonatal immune challenge on behaviours relating to anxiety in the adult.

Febrile seizures and temporal lobe epileptogenesis.

Febrile seizures (FS) are a common neurological disorder that affects children. Simple FS are thought to be benign but experimental and clinical evidence support that the risk of developing epilepsy after FS increases if the FS are prolonged and the brain is abnormal. In addition, prolonged FS (PFS) have many deleterious long-term effects characterized mainly in the hippocampus but may involve the whole brain and that prompt abortive treatment of PFS may prevent some of the adverse effects. This review focuses on some of the key factors involved in the generation of FS, factors leading to PFS and potential mechanisms and functional correlates leading to temporal lobe epilepsy (TLE).

The role of interleukin-1beta in febrile seizures.

Febrile seizures (FS) occur in children as a result of fever. Despite their prevalence, the pathophysiology of FS has remained unclear. Recent evidence from clinical and experimental studies has highlighted a potential role of immune generated products in the genesis of FS. Of particular interest are the pro-inflammatory cytokine, interleukin-1beta (IL-1beta) and its naturally occurring antagonist, interleukin 1 receptor antagonist (IL-1ra). Using a novel animal model of FS, involving the generation of physiological fever, we investigated the role of the IL-1beta/IL-1ra system in the genesis of FS. We found that animals with FS had increased hippocampal and hypothalamic IL-1beta compared to equally treated animals without FS, which was first evident at onset of FS in the hippocampus. There were no differences in IL-1ra levels. ICV IL-1beta increased the number of animals with FS while IL-1ra had an opposite anti-convulsant effect. The data from these studies, in combination with recent results from other laboratories, have established a putative role for the IL-1beta/IL-1ra system in the genesis of FS.

Separating kindling and LTP: lessons from studies of PKM zeta in developing and adult rats.

The kindling model of temporal lobe epilepsy (TLE) and the memory model of long-term potentiation (LTP) may have common underlying mechanisms. This is evident by the demonstration that certain signaling molecules play a key role in both. Recently, a brain specific isoform of protein kinase C (PKMzeta) has been shown to play a significant role in both maintaining LTP and memory storage. We were interested in determining if this kinase had a crossover role in kindling-induced epileptogenesis. Using developing and adult rats we examined the role of PKMzeta in kindling. In developing (P15) rats we determined the effect of PKMzeta on retention of amygdala kindling and kindling rate by intra-amygdala administration of a selective PKMzeta antagonist, ZIP (10 nmol). In adult rats we examined the effect of PKMzeta inhibition, ZIP (10 nmol), on after discharge (AD) thresholds and kindling retention using rapid hippocampal kindling. Inhibition of PKMzeta by the antagonist ZIP did not affect kindling rate or retention in developing rats. In addition there was also no observed effect on AD thresholds and kindling retention in adult rats. Our results show that, despite the similarities between kindling and LTP in their induction, there is dissociation in the role that PKMzeta plays within the two in maintenance. This may be of importance in establishing a separation between the pathophysiological processes involved in sustaining kindling and the physiological mechanisms involved in maintaining LTP and memory storage.

Age-dependent consequences of status epilepticus: animal models.

Status epilepticus (SE) is a significant neurological emergency that occurs most commonly in children. Although SE has been associated with an elevated risk of brain injury, it is unclear from clinical studies in whom and under what circumstances brain injury will occur. The purpose of this review is to evaluate the effects of age on the consequences of SE. In this review, we focus mainly on the animal data that describe the consequences of a single episode of SE induced in the adult and immature rat brain. The experimental data suggest that the risk of developing SE-induced brain damage, subsequent epilepsy and cognitive deficits in large part depends on the age in which the SE occurs. Younger rats are more resistant to seizure-induced brain damage than older rats; however, when SE occurs in immature rats with abnormal brains, there is an increase in the severity of seizure-induced brain injury. Better understanding of the pathophysiologic mechanisms underlying the age-specific alterations to the brain induced by SE will lead to the development of novel and effective strategies to improve the deleterious consequences.

Causal links between brain cytokines and experimental febrile convulsions in the rat.

PURPOSE: Despite the prevalence of febrile convulsions (FCs), their pathophysiology has remained elusive. We tested the hypothesis that components of the immune response, particularly the proinflammatory cytokine interleukin-1beta (IL-1beta) and its naturally occurring antagonist interleukin-1 receptor antagonist (IL-1ra) may play a role in the genesis of FC. METHODS: Postnatal day 14 rats were treated with lipopolysaccharide (LPS; 200 microg/kg, i.p.) followed by a subconvulsant dose of kainic acid (1.75 mg/kg, i.p.). Brains were harvested at and 2 h after onset of FCs to measure brain levels of IL-1beta and IL-1ra. Separate groups of animals were given intracerebroventricular (ICV) injections of IL-1beta, or IL-1ra in an attempt to establish a causal relation between the IL-1beta/IL-1ra system and FCs. RESULTS: Animals with FCs showed increased IL-1beta in the hypothalamus and hippocampus but not in the cortex compared with noFC animals that also received LPS and kainic acid. This increase was first detected in the hippocampus at onset of FCs. No detectable difference in IL-1ra was found in brain regions examined in either group. When animals were treated with IL-1beta ICV, a dose-dependant increase was noted in the proportion of animals that experienced FCs, whereas increasing doses of IL-1ra, given to separate groups of animals, were anticonvulsant. CONCLUSIONS: Our results suggest that excessive amounts of IL-1beta may influence the genesis of FCs. This may occur by overproduction of IL-1beta, or by alteration in the IL-1beta/IL-1ra ratio in the brain after an immune challenge.

Febrile convulsions induced by the combination of lipopolysaccharide and low-dose kainic acid enhance seizure susceptibility, not epileptogenesis, in rats.

PURPOSE: Febrile convulsions (FCs) are seizures that occur as a result of fever. Retrospective clinical studies show a large percentage of adults with temporal lobe epilepsy have a positive history of FCs, but it is unknown whether FCs during infancy alter susceptibility to developing late epilepsy. We have tested the hypothesis that FCs affect seizure susceptibility and epileptogenesis in adults. METHODS: A novel model of FCs was used, in which lipopolysaccharide (LPS, Escherichia coli), in combination with a subconvulsant dose of kainic acid, caused FCs in 50% of 14-day-old male rats. Eight to 10 weeks later, electrodes were implanted into the basolateral amygdalae of all rats. After completion of the kindling procedure, animals were killed and brains examined for neurodegeneration by using Fluoro-Jade histochemistry. RESULTS: Amygdala stimulation revealed that rats that had a FC as pups had lower afterdischarge thresholds and longer afterdischarge durations when compared with rats that received the same treatment but did not convulse. Despite this, when kindled daily, rats that had FCs as pups kindled at the same rate as did controls. However, an increase in the number of degenerating neurons was noted within the hippocampus of rats with a previous FC. CONCLUSIONS: These results suggest that, although FCs during infancy can reduce seizure thresholds, it does not facilitate epileptogenesis in adulthood. Our results indicate that FCs affected local circuits in the amygdala and possibly in the hippocampus but not circuits responsible for seizure generalization.

Lipopolysaccharide-induced febrile convulsions in the rat: short-term sequelae.

PURPOSE: Febrile convulsions (FCs) occur in children as a result of fever. The mechanisms involved in the genesis of FCs and their long-term consequences on brain development remain unclear. We have developed a model of FC, by using fever as a parameter, to test the hypothesis that fever can lower seizure threshold and to examine the neurologic sequelae of FCs. METHODS: Fourteen-day-old rat pups equipped with body-temperature telemetry devices exhibited approximately 1.5 degrees C fevers after lipopolysaccharide (Escherichia coli, 200 microg/kg). During such fevers, concurrently administered doses of kainic acid that are normally subconvulsant were used to induce convulsions with fever. Animals were then killed at varying times for pathological and immunohistochemical studies. RESULTS: The pairing of lipopolysaccharide and subconvulsant kainic acid resulted in convulsions in approximately 50% of febrile animals, with very low mortality. To study the neural correlates of these FCs, we used fos immunohistochemistry and found that animals with FCs had fos-positive immunoreactivity in brain regions involved in seizures. After a period of 72 h, we also examined brains for pathologic changes and found no differences among our groups. CONCLUSIONS: Our data indicate that a neuroimmune challenge and its accompanying fever reduce the seizure threshold. Furthermore, the FCs induced by fever in this model do not have short-term adverse effects on the brain. In addition, this model, by incorporating physiologic fever, may be useful for examining the role of fever and its constituent mediators in the genesis of FCs.