Seizures in the Developing Brain

Abstract

Summary:Purpose: Development and sex hormones are important determinants of seizure susceptibility. Seizures develop in the immature brain more readily than in the mature brain. Male children experience a higher incidence of epilepsy or unprovoked seizures than do female children. Sex-specific differences in the development of seizure-suppressing neuronal networks may account, at least in part, for this increased age-and sex-related susceptibility to seizures. The control of seizures can be influenced by the substantia nigra pars reticulata (SNR) in an age-and sex-specific manner. In the adult male rat SNR, two topographically discrete regions (SNRanterior and SNRposterior) mediate distinct effects on seizures, by using divergent output networks in response to localized infusions of γ -aminobutyric acid (GABA)A agents, such as muscimol. The GABAA-sensitive "anticonvulsant" region is located in the SNRanterior, whereas the GABAA-sensitive "proconvulsant region is in the SNRposterior. In immature postnatal day (PN)15-21 male rats, the SNR is not topographically segregated, and GABAAergic drug infusions produce similar effects when applied in the SNRanterior or SNRposterior. Only a GABAA-sensitive proconvulsant network is evident. By contrast, female SNR does not contain any region that mediates muscimol-related proconvulsant effects. As with the adult, immature female rats do not develop a proconvulsant SNR region at any age.Methods: We measured the effects of SNR muscimol infusions on seizures in male rats castrated at birth to better understand the effects of testosterone on the formation of age-and sex-specific features of the SNR.Results: Neonatal castration permanently alters the maturation of the muscimol-sensitive SNR effect on seizures. The SNR of neonatally castrated rats develops functionally like the "female" SNR. The "proconvulsant" SNR region does not develop in the absence of testosterone in the immediate postnatal period. The "male" type of SNR effects can be induced in neonatally castrated rats by restoration of testosterone levels or in female rats by artificially increasing testosterone levels. Dihydrotestosterone and estrogen, produced by the reduction and aromatization of testosterone, respectively, are the direct mediators of testosterone actions. At PN0, only β estrogen receptors are equally expressed in the SNRs of males and females and may be responsible for testosterone-mediated effects in both sexes.Conclusions: The phenotype of SNR GABAergic neurons, as characterized by GABAA-receptor subunit composition, by muscimol-induced electrophysiologic responses, and by connectivity of output networks each may be altered by the presence of testosterone. Higher KCC2 messenger RNA (mRNA) expression in female PN15 SNR neurons compared with males may be responsible for sex-related differences in muscimolinduced electrophysiologic responses. In summary, a growing body of compelling evidence identifying sex-related differences in the SNR implicates postnatal testosterone as a critical factor in the dev...

Long-term outcomes in patients with West syndrome: An outpatient clinical study

“…A study on rat pups showed that sex hormones can affect epileptogenesis in the developing brain, and that the immature brain of males is more vulnerable to the insult than the female brain [20]. This may provide some support for the Table 2 Characteristics of epilepsy and neuro-developmental/social outcomes.…”

A New Rat Model of Epileptic Spasms Based on Methylazoxymethanol-Induced Malformations of Cortical Development

“…The age-specific difference in spasm susceptibility observed in MAM-exposed rats following a single NMDA dose also suggests a parallel age-dependent change in neuronal or network excitability. Indeed, susceptibility to seizures changes over the postnatal development with the development of neural circuits (31, 32). The immature MCD brain may exhibit a time window of over-excitation during development, which appeared to be at P12–P13 in our model based on peak NMDA response.…”

Severe Hypoglycemia in a Juvenile Diabetic Rat Model: Presence and Severity of Seizures Are Associated with Mortality

“…Impaired awareness is particularly prevalent when the age of diabetes diagnosis is early (<6 years) and is associated with recurrent hypoglycemic episodes resulting in seizures or coma [48] though other studies have reported conflicting results [18], [20]. In addition, animal studies have demonstrated the increased susceptibility of the juvenile brain to neuronal excitability and seizures [34], [36], [49] and shorter latency to seizure generalization [45]. While there are several clinical studies that have assessed the effects of seizures such as EEG abnormalities [37] and increased cognitive impairmanet [50], the specific incidence of hypoglycemic seizures is unknown.…”