For the past 35 years, I have been involved in work across the range of problems associated with developmental epilepsy. These projects include: (1) Developing a model of infantile spasms, a devastating seizure syndrome of infancy that has catastrophic consequences. (2) Mechanisms and models of idiopathic generalized epilepsy/juvenile myoclonic epilepsy (in collaboration with Dr. Greenberg, Nationwide’s Children’s Hospital, Columbus, OH). (3) Effects of prenatal corticosteroid exposure on postnatal seizure susceptibility and its relevance to autistic behaviors. (4) Seizure syndrome elicited by a neurotoxin tetramethylenedisulfotetramine (tetramine, TMDT) as well as development of effective countermeasures (in collaboration with Dr. Shakarjian, School of Health Sciences and Practice, NYMC).
Department of Cell Biology & Anatomy
Basic Sciences Building, Room A20
Valhalla, NY 10595
For 20 years my lab has been engaged in work across the range of problems associated with research in developmental epilepsy:
(1) Developing and validation of a model of infantile spasms, a devastating seizure syndrome of infancy with specific features and therapies, and catastrophic consequences. We were the first to develop and validate a viable rodent model of infantile spasms that can be used for testing of new treatment approaches. This model stems from our previous work investigating the effects and mechanisms of prenatal exposure to synthetic corticosteroids. We noted that prenatal exposure to synthetic corticosteroids on top of postnatal behavioral changes also alters postnatal levels of cortisol and ACTH in experimental animals reproducing thus findings in patients with infantile spasms. In the model, prenatal priming with synthetic corticosteroids provides a background for postnatal development of spasms after a trigger with NMDA during developmentally specific period. Resulting flexion spasms with semiology similar to human spasms have similar electrographic features, and do respond to the principal therapy of infantile spasms, i.e., ACTH. Our recent work identified that prenatal stress has similar effects as prenatal exposure to synthetic corticosteroids in terms of priming the brain for postnatal expression of changes. We were also able to determine that additional melanocortin-derived peptides (besides ACTH) may be the powerful tools in treatment of infantile spasms. The model has been expanded to mice and most recently we determined that medial hypothalamic nuclei play a significant role in the control of spasms.
(2) Mechanisms and models of idiopathic generalized epilepsy/juvenile myoclonic epilepsy (JME, a common epilepsy in teenage years and twenties). In collaboration with Dr. David Greenberg, we study mouse model of idiopathic generalized epilepsy using mice hemizygous for Brd2 gene, a prominent gene associated with and linked to idiopathic generalized epilepsy in humans. We have determined that one of the culprits for the occurrence of spontaneous seizures in these mice may be downregulation of inhibitory neurotransmitter GABA along the basal ganglia pathway. Further we found, that this decline in GABAergic neurons is developmental and may be specific for limited subpopulation of GABAergic neurons, the parvalbumin immunopositive GABA neurons. We also determined behavioral phenotype of Brd2 hemizygous mice, which in many aspects is similar to human juvenile myoclonic epilepsy personality.
(3) Molecular mechanisms of prenatal corticosteroid exposure in the postnatal seizure susceptibility and behavioral outcome and its relevance for autistic behaviors. Human studies indicate that severe stress during specific time windows in pregnancy may be associated with increased risk for development of autism in the children born in those pregnancies. Similarly, children with infantile spasms develop autism in 30-40% of cases. As our model of infantile spasms is based on prenatal priming with betamethasone or stress, we focused on recording of autistic features in rats after prenatal exposure to excess corticosteroids as well as on the changes in their transcriptome.
(4) Together with Dr. Shakarjian (School of Health Sciences and Practice, NYMC) we are exploring neurotoxic syndrome induced by a powerful synthetic toxin tetramethylenedisulfotetramine (tetramine, TMDT). The purpose of our research is to determine features of the TMDT-induced seizure syndrome in normal and vulnerable (immature, developing, female) populations and find effective antidotes, because there is no available treatment.
Methods used in the lab include in vitro electrophysiology (extracellular and patch clamp), western blot, PCR, autoradiography, histology, immunohistochemistry, intracranial drug administration, long-term video/EEG monitoring of seizures and sleep, behavioral testing (learning, memory, anxiety, autistic traits, motor behaviors), and microarray RNA profiling with transcriptome analysis.
Behavioral Phenotyping Core Facility:
We have established a Behavioral Phenotyping Core Facility for mice and rats to determine changes in behavioral phenotypes based on the genome, action of drugs, or environmental changes. The facility is available to NYMC investigators and to outside of institution collaborators (currently Dr. Osten, Cold Spring Harbor Labs; Dr. Goldfarb, Hunter College; Dr. Chia, Albert Einstein College of Medicine; Dr. Mishra, Rutgers).
I am serving as an Associate Editor for Neuroreport as well as for Cellular and Molecular Epilepsy. I am a Contributing Editor for Basic Science in Epilepsy Currents and a member of editorial board of Epilepsy Research.
Graduate Degree: M.D., Ph.D.
Graduate Degree Institution: Faculty of General Medicine of the Charles University, Prague, Czechoslovakia, 1984 (M.D.), Human Physiology, Czechoslovak Academy of Sciences, Prague, Czechoslovakia, 1989 (Ph.D.)