Steroid hormonal regulation is critical for normal brain development and may play an important role in human seizure disorders. The substantia nigra pars reticulata (SNR) is one of the structures controlling the spread of seizure activity via its GABAergic neurotransmission especially through GABAA receptors. The SNR is functionally subdivided into anterior and posterior regions which mediate opposing effects of muscimol (a GABAA receptor agonist) on fluorothyl seizures. Muscimol infusions in the SNRanterior produce anticonvulsant effects, while similar infusions in the SNRposterior produce proconvulsant effects. Preliminary data show that the functional maturation of these two SNR regions may be under gonadal steroid hormonal control. In neonatally castrated m ale rats there is accelerated maturation of the """"""""anticonvulsant"""""""" SNRanterior. Neonatal castration does not influence the emergence of the """"""""proconvulsant"""""""" SNR region. Furthermore, in female rats there is no functional segregation of the SNR because muscimol infusions produce anticonvulsant effects irrespective to injection site. Therefore, the presence of testosterone early in life may be responsible for the functional segregation of the SNR. The following hypotheses will be tested: In male rats, early postnatal depletion of testosterone accelerates the development of the """"""""anticonvulsant"""""""" SNRanterior region. In male rats, the emergence of the """"""""proconvulsant"""""""" SNRposterior region is independent of early postnatal testosterone. The two SNR regions in neonatally castrated rats have similar features as the two SNR regions in normal male rats (the term features denotes responsivity to GABAergic agents and output networks). Lack of prenatal testosterone leads to the female type of the SNR with only one GABAA sensitive SNR region. The female SNR may have similar features with the mature male """"""""anticonvulsant"""""""" SNRanterior. The prenatal testosterone surge is responsible for the development of the """"""""proconvulsant"""""""" SNR region. Methods include early postnatal castration and hormone replacements, localized infusions of GABAA agonists and antagonists, flurothyl seizure testing and [14C] deoxyglucose autoradiography. Rats of both sexes and various ages will be used. These studies may lead to the development of new antiepileptic treatments that take into the account sexual age-related differences.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
Application #
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Fureman, Brandy E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Albert Einstein College of Medicine
Schools of Medicine
United States
Zip Code
Coppola, Antonietta; Moshé, Solomon L (2009) Why is the developing brain more susceptible to status epilepticus? Epilepsia 50 Suppl 12:25-6
Velisek, Libor (2006) CNS aspects of prenatal drug exposure: drugs of abuse, toxins, and corticosteroids. Ann N Y Acad Sci 1074:577-89
Velisek, Libor; Veliskova, Jana; Giorgi, Filippo S et al. (2006) Sex-specific control of flurothyl-induced tonic-clonic seizures by the substantia nigra pars reticulata during development. Exp Neurol 201:203-11
Veliskova, J (2006) The role of estrogens in seizures and epilepsy: the bad guys or the good guys? Neuroscience 138:837-44
Ravizza, Teresa; Rizzi, Massimo; Perego, Carlo et al. (2005) Inflammatory response and glia activation in developing rat hippocampus after status epilepticus. Epilepsia 46 Suppl 5:113-7
Velisek, Libor; Veliskova, Jana; Ravizza, Teresa et al. (2005) Circling behavior and [14C]2-deoxyglucose mapping in rats: possible implications for autistic repetitive behaviors. Neurobiol Dis 18:346-55
Veliskova, Jana; Miller, Alexandra M; Nunes, Magda L et al. (2005) Regional neural activity within the substantia nigra during peri-ictal flurothyl generalized seizure stages. Neurobiol Dis 20:752-9
Veliskova, J (2004) [Effects of sex hormones in the CNS] Cesk Fysiol 53:66-75
Ravizza, Teresa; Friedman, Linda K; Moshe, Solomon L et al. (2003) Sex differences in GABA(A)ergic system in rat substantia nigra pars reticulata. Int J Dev Neurosci 21:245-54
Ravizza, T; Veliskova, J; Moshe, S L (2003) Testosterone regulates androgen and estrogen receptor immunoreactivity in rat substantia nigra pars reticulata. Neurosci Lett 338:57-61

Showing the most recent 10 out of 33 publications