Ellen F. Sperber

Resistance of the immature hippocampus to seizure-induced synaptic reorganization

Temporal lobe epilepsy is a common form of epilepsy in human adults and is associated with a unique pattern of damage in the hippocampus. The damage includes cell loss of the CA3 and CA4 areas and synaptic growth (sprouting) of mossy fibers in the supragranular layer of the dentate gyrus. Experimental evidence indicates that in adult rats the excitatory amino acid, kainic acid, induces a similar pattern of changes in hippocampal circuitry associated with alterations in perforant path excitation and inhibition. It has been suggested that, in humans, this type of damage may be a result of seizures early in life. In this study we examined the effects of kainic acid-induced status epilepticus on synaptic reorganization and paired-pulse electrophysiology in developing rats and adults. Kainic acid induced more severe seizures in 15-day-old rat pups than in adults. In contrast to adult rats, these seizures did not produce CA3/CA4 neuronal loss, mossy fiber sprouting or changes in paired-pulse excitation or inhibition in the hippocampus of rat pups tested 2-4 weeks after status epilepticus. Our results provide evidence that the immature hippocampus may be more resistant to seizure-induced changes than the mature hippocampus.

Neuroprotective Effects of Estrogens on Hippocampal Cells in Adult Female Rats After Status Epilepticus

Summary: Purpose: Estrogens have neuroprotective effects in ischemia, stroke, and other conditions leading to neuronal cell death (e.g., Alzheimers disease). The present study examined whether estrogens may have neuroprotective effects after seizures.

Neuronal Migration Disorders Increase Susceptibility to Hyperthermia‐Induced Seizures in Developing Rats

Summary: Purpose: Retrospective studies suggest that adult patients with intractable epilepsy may have a history of febrile seizures in childhood. Risk factors for a febrile seizure may include the rate of increase in the core temperature (T‐core), its peak (Tmax), the duration of the temperature increase, or an underlying brain pathology. Recently, neuronal migration disorders (NMD) have been diagnosed with increasing frequency in patients with epilepsy, but the link between NMD, febrile seizures, and epilepsy is unclear. We studied rat pups rendered hyperthermic to ascertain the incidence of seizures, mortality, and extent of hippocampal cell loss in each group.

Kindling in developing animals: expression of severe seizures and enhanced development of bilateral foci

In adult rats, alternating stimulations between two limbic sites can result in one site kindling normally, while the other is retarded in an early non-generalized kindling stage. This phenomenon has been named kindling antagonism. In this report, we present data indicating that kindling antagonism does not occur in 16-day-old rats. Instead, 16-day-old rats receiving alternating stimulations in the amygdala and hippocampus develop progressively more severe seizures. Kindling with alternate stimulations is elicited at a much faster rate at the two foci compared to kindling from a single site, either the hippocampus or amygdala. All groups develop generalized seizures including seizure stages 6 and 7, consisting of wild jumping, running with vocalizations and tonus. These seizures appear after relatively few stimulations in the pup, in comparison to the adult. The results indicate that the immature brain is less able to suppress the generalization of seizures than the adult. The age-specific enhanced development of bilateral foci may be due to underdeveloped inhibitory systems and may underlie the propensity of the immature CNS to develop multifocal seizures.

Hippocampal sclerosis revisited

Studies dating back more than 150 years reported a relationship between hippocampal sclerosis and epilepsy. Retrospective studies of patients who underwent temporal lobectomy for intractable partial epilepsy found a relationship between a history of early childhood convulsions, hippocampal sclerosis, and the development of temporal lobe epilepsy. Many believe that febrile seizures lead to hippocampal damage and this in turn predisposes the patient to the development of temporal lobe epilepsy. Studies in adult rats have shown that seizures can lead to hippocampal damage and unprovoked recurrent seizures. However, many questions remain as to the relevance of early childhood seizures to hippocampal sclerosis and temporal lobe epilepsy. Human prospective epidemiologic studies have not shown a relationship between early childhood seizures and temporal lobe epilepsy. Recent MRI studies in humans suggest that a preexisting hippocampal lesion may predispose infants to experience febrile seizures, later on hippocampal sclerosis, and possibly temporal lobe epilepsy may occur. Unlike the studies in adult rats, normal immature rats with seizures have not been shown to develop hippocampal damage or unprovoked seizures in adulthood. Furthermore, animal studies reveal that preexisting brain abnormalities can predispose to hippocampal damage following seizures early in life. This paper reviews evidence for and against the view that early childhood convulsions, hippocampal sclerosis, and temporal lobe epilepsy are related, while also exploring clinical and animal studies on how seizures can lead to hippocampal damage, and how this can result in temporal lobe epilepsy. By better understanding the cause and effect relationship between early childhood seizures and hippocampal injury in normal and abnormal brains specific treatments can be developed that target the pathogenesis of epilepsy.

Evidence for the involvement of nigral GABAB receptors in seizures of rat pups

Several studies have implicated the substantia nigra GABAergic system in the mediation of seizures in adult rats. The present study examines whether the different GABA receptors (GABAA and GABAB), are preferentially involved in this GABAergic seizure suppression mechanism. Adult rats were intranigrally infused with muscimol (GABAA receptor agonist), bicuculline (GABAA receptor antagonist) or baclofen (GABAB receptor agonist) and were exposed to flurothyl seizures. Results indicated that while infusions of muscimol had an anticonvulsant effect, infusions of bicuculline had a proconvulsant effect. Baclofen infusions were found to have no effect on seizures. These findings suggest an involvement of the nigral GABAA receptors in the mediation of seizures in adult rats.

Age-related differences in seizure susceptibility to flurothyl.

The purpose of the present study was to determine whether the susceptibility to seizures induced by inhalation of flurothyl ether (FE) varies with age. Adult rats and 16-day-old rat pups were tested in different sized chambers to also determine whether the size of the FE-test chamber influences seizure thresholds. Results indicate that pups developed age-specific seizure patterns; their seizure latency thresholds were shorter than those of adult animals. For both age-groups, seizure thresholds varied as a function of chamber size; the smaller the chamber the faster seizures occurred.

Maturation and segregation of brain networks that modify seizures.

The mature brain is less susceptible to seizures than the immature brain. We demonstrate that in the mature substantia nigra (SN) there are two topographically discrete GABAA-sensitive regions which differ in the amount of mRNA expression of the GABAA receptor alpha 1 subunit. These two regions mediate separate anticonvulsant and proconvulsant effects and use divergent projection networks. By contrast, in the immature SN there is no special topography of mRNA expression of the alpha 1 subunit and only the proconvulsant network is present. The decreased seizure susceptibility of the mature brain may be related to postnatal segregation of GABAA-sensitive networks.

Transplacentally induced neuronal migration disorders: An animal model for the study of the epilepsies

Recent clinical and laboratory data suggest that there is a link between neuronal migration disorders (NMD) and increased seizure threshold. To characterize an animal model with features similar to human NMD and to assess seizure susceptibility, NMD were induced in the rat at the time of neuroblastic division (PG15) and three other gestational ages (PG 13, PG14, PG16) by transplacental exposure to methylaxozymethanol (MAM, 25 mg/kg). Offspring pups were monitored for spontaneous and electrographic seizures. At postnatal day 14, randomly selected rat pups were sacrificed for histological examination. In other MAM‐exposed pups and controls, status epilepticus was induced by intraperitoneal administration of kainic acid.

Nigral infusions of muscimol or bicuculline facilitate seizures in developing rats

The substantia nigra (SN) appears to be a crucial site involved in the modification of seizures. The aim of this study was to elucidate the role of the GABA nigral system in the expression of seizures by comparing the effects of multiple doses of a GABA agonist (muscimol) and a GABA antagonist (bicuculline methobromide) on the development of flurothyl seizures in 16-day-old rat pups. The drugs were infused bilaterally either in the SN or dorsal to the SN. An additional group of pups were infused with bicuculline in the corpus striatum. Results indicate that both drugs facilitated the development of seizures in a dose-related manner when infused into the SN. Infusions of muscimol dorsal to the SN had no effect on seizure latencies while infusions of bicuculline dorsal to SN or corpus striatum still increased the susceptibility of rat pups to seizures. The data suggest that only the effects of muscimol on seizures are specific for the SN and that early in life muscimol may exert its proconvulsant effects via a different receptor site or mechanism than bicuculline.