Seizures in the developing brain

Jana Velíšková, Olga I. Claudio, Aristea S. Galanopoulou, Fred A. Lado, Teresa Ravizza, Libor Velíšek, Solomon L. Moshe

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

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 PNO, 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 muscimol-induced 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 development of pro- or anticonvulsant circuits. The recognition of sex- and age-related features in the SNR holds the promise that these findings can be translated into the development of specific and effective treatments for seizure disorders.

Original languageEnglish (US)
Pages (from-to)6-12
Number of pages7
JournalEpilepsia
Volume45
Issue numberSUPPL. 8
DOIs
StatePublished - 2004

Fingerprint

Seizures
Brain
Testosterone
Muscimol
Sex Characteristics
Pars Reticulata
Anticonvulsants
Epilepsy
GABA Agents
Aminobutyrates
Safe Sex
GABAergic Neurons
Dihydrotestosterone
Castration
Gonadal Steroid Hormones
GABA-A Receptors
Estrogen Receptors
Estrogens
Parturition
Phenotype

Keywords

  • Development
  • Epilepsy
  • GABA
  • Seizures
  • Sex
  • Substantia nigra
  • Testosterone

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

Cite this

Velíšková, J., Claudio, O. I., Galanopoulou, A. S., Lado, F. A., Ravizza, T., Velíšek, L., & Moshe, S. L. (2004). Seizures in the developing brain. Epilepsia, 45(SUPPL. 8), 6-12. https://doi.org/10.1111/j.0013-9580.2004.458002.x

Seizures in the developing brain. / Velíšková, Jana; Claudio, Olga I.; Galanopoulou, Aristea S.; Lado, Fred A.; Ravizza, Teresa; Velíšek, Libor; Moshe, Solomon L.

In: Epilepsia, Vol. 45, No. SUPPL. 8, 2004, p. 6-12.

Research output: Contribution to journalArticle

Velíšková, J, Claudio, OI, Galanopoulou, AS, Lado, FA, Ravizza, T, Velíšek, L & Moshe, SL 2004, 'Seizures in the developing brain', Epilepsia, vol. 45, no. SUPPL. 8, pp. 6-12. https://doi.org/10.1111/j.0013-9580.2004.458002.x
Velíšková J, Claudio OI, Galanopoulou AS, Lado FA, Ravizza T, Velíšek L et al. Seizures in the developing brain. Epilepsia. 2004;45(SUPPL. 8):6-12. https://doi.org/10.1111/j.0013-9580.2004.458002.x
Velíšková, Jana ; Claudio, Olga I. ; Galanopoulou, Aristea S. ; Lado, Fred A. ; Ravizza, Teresa ; Velíšek, Libor ; Moshe, Solomon L. / Seizures in the developing brain. In: Epilepsia. 2004 ; Vol. 45, No. SUPPL. 8. pp. 6-12.
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TY - JOUR

T1 - Seizures in the developing brain

AU - Velíšková, Jana

AU - Claudio, Olga I.

AU - Galanopoulou, Aristea S.

AU - Lado, Fred A.

AU - Ravizza, Teresa

AU - Velíšek, Libor

AU - Moshe, Solomon L.

PY - 2004

Y1 - 2004

N2 - 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 PNO, 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 muscimol-induced 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 development of pro- or anticonvulsant circuits. The recognition of sex- and age-related features in the SNR holds the promise that these findings can be translated into the development of specific and effective treatments for seizure disorders.

AB - 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 PNO, 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 muscimol-induced 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 development of pro- or anticonvulsant circuits. The recognition of sex- and age-related features in the SNR holds the promise that these findings can be translated into the development of specific and effective treatments for seizure disorders.

KW - Development

KW - Epilepsy

KW - GABA

KW - Seizures

KW - Sex

KW - Substantia nigra

KW - Testosterone

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