Faculty: O. Carter Snead III, MD
Professor of Pediatrics and Medicine (Neurology)
Head of Neurology,
Director of the Centre for Brain & Behavior
Hospital for Sick Children
General Research Area: Neuropharmacology
Basic Mechanisms of Epileptogenesis
The goal of my laboratory is to develop animal models of epilepsy syndromes that are unique to children, and to investigate mechanisms of epileptogenesis in these models. We defined and standardized the g-hydroxybutyrate (GHB) rat model of generalized absence seizures which is now utilized world wide to screen for anti absence activity of putative antiepileptic compounds and to investigate basic mechanisms of absence seizures. We have shown that GABAB receptor (GABABR) agonists exacerbate, that both GHB and GABABR antagonists block, experimental absence seizures. More recently, we have developed, characterized, and standardized an animal model of atypical absence epilepsy in rat and mouse. This model is created by inhibiting cholesterol synthesis in the brain by AY 9944 (AY) during postnatal brain development. Atypical absence seizures in children are a component of epilepsy syndromes in children which are hard to treat and which have a very poor neurodevelopmental outcome. The AY model of atypical absence epilepsy in rat is clinically relevant because it reliably and accurately mirrors the EEG, behavioural, pharmacological, and developmental characteristics of the human condition. Recently we have created mutant mice that over-express the GABA(B) receptor R1 subunit and shown that these animals show a phenotype consistent with atypical absence seizures. We are currently investigating GABA(B) receptor-mediated mechanisms within thalamohippocampal circuitary in this genetic animal model of atypical absence seizures.
Cortez MA, Shen L, Wu Y, Aleem IS, Trapanier CH, Sadeghnia HR, Ashraf A, Kanawaty A, Liu CC, Stewart LS, Snead OC. Infantile spasms and Down syndrdome: a new animal model. Pediatr Res 2009 [E pub ahead of print].
Nylen K, Perez-Velazquez JL, Sayed V, Gibson KM, Burnham WM. Snead OC. The ketogenic diet increases the number of mitochondria in Aldh5a1-/- mice but has no effect on GHB or GABA levels. Biochem Biophys Acta 2009 [E pub ahead of print].
Stewart LS, Ying Wu, Eubanks J, Han A, Leschenko Y, Perez Velazquez, JL, Cortez MA, Snead OC. Mice over-expressing GABABR1b receptor subtype show evidence of an atypical absence seizure phenotype. Epilepsy and Beh. 2009 In Press [E pub ahead of print].
Widjaja E, Mahmoodabadi Z, Otsubo H, Snead OC, Holowka S, Bells S, Raybaud C. Subcortical alterations in tissue microstructure adjacent to focal cortical dsplasia: detection at diffusion-tensor MR imaging by using magnetoencephalographic dipole cluster localization. Radiology; 2009 [Epub ahead of print].
Huo JZ, Cortez MA, Wu Y, Snead OC. The role of lipid reafts in epileptogenesis in the AY9944 model of atypical absence seizures. Epilepsia. 2009 [Epub ahead of print].
Bercovici E, Cortez MA, Wang X, Snead OC. Monoamine variability in the chronic model of atypical absence seizures. Epilepsia. 2008 Nov 19.[Epub ahead of print].
Galicia E, Imai K, Mohamed IS, Go C, Fujimoto A, Ochi A, Sakuta R, Halliday W, Rutka JT, Chuang SH, Snead OC, Otsubo H. Changing Ictal onset EEG patterns in children with cortical dysplasia. Brain Dev. 2009 [E-pub ahead of print].
Ishii R, Canuet L, Ochi A, Xiang J, Imai K, Chan D, Iwase M, Takeda M, Galicia E, Imai K, Mohamed IS, Go C, Fujimoto A, Ochi A, Sakuta R, Halliday W, Rutka JT, Chuang SH, Snead OC, Otsubo H. Changing Ictal onset EEG patterns in children with cortical dysplasia. Brain Dev . 2009 [E-pub ahead of print].
Hospital For Sick Children
Division of Neurology
Hospital for Sick Children
555 University Avenue