1. Convulsive seizures from experimental focal cortical dysplasia occur independently of cell misplacement
- Author
-
Gordon F. Buchanan, Felicia A. Harrsch, Yuegao Huang, Lawrence S. Hsieh, Kumiko Claycomb, Fahmeed Hyder, John H. Wen, Angélique Bordey, and Janice R. Naegele
- Subjects
Male ,0301 basic medicine ,Science ,Green Fluorescent Proteins ,Prefrontal Cortex ,General Physics and Astronomy ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,White matter ,Mice ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,Cell Movement ,Genes, Reporter ,Seizures ,medicine ,Animals ,Humans ,Cognitive Dysfunction ,Prefrontal cortex ,PI3K/AKT/mTOR pathway ,Neurons ,Sirolimus ,Multidisciplinary ,TOR Serine-Threonine Kinases ,General Chemistry ,Cortical dysplasia ,medicine.disease ,White Matter ,3. Good health ,Malformations of Cortical Development ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Heterotopia (medicine) ,Gene Expression Regulation ,Female ,Neuroscience ,Neurocognitive ,030217 neurology & neurosurgery ,Signal Transduction ,medicine.drug - Abstract
Focal cortical dysplasia (FCD), a local malformation of cortical development, is the most common cause of pharmacoresistant epilepsy associated with life-long neurocognitive impairments. It remains unclear whether neuronal misplacement is required for seizure activity. Here we show that dyslamination and white matter heterotopia are not necessary for seizure generation in a murine model of type II FCDs. These experimental FCDs generated by increasing mTOR activity in layer 2/3 neurons of the medial prefrontal cortex are associated with tonic-clonic seizures and a normal survival rate. Preventing all FCD-related defects, including neuronal misplacement and dysmorphogenesis, with rapamycin treatments from birth eliminates seizures, but seizures recur after rapamycin withdrawal. In addition, bypassing neuronal misplacement and heterotopia using inducible vectors do not prevent seizure occurrence. Collectively, data obtained using our new experimental FCD-associated epilepsy suggest that life-long treatment to reduce neuronal dysmorphogenesis is required to suppress seizures in individuals with FCD., The etiology of focal cortical dysplasia (FCD) is not fully understood. Here authors generate an mTORC1 overactivation mouse model that recapitulates hallmarks of type II FCDs, including spontaneous seizures, and suggest that neuronal defects, rather than macrostructural changes, lead to seizures.
- Published
- 2016