Increased excitability and decreased sensitivity to GABA in an animal model of dysplastic cortex.
OBJECTIVE
Cortical dysplasia (CD) is associated with epilepsy in both the pediatric and adult populations. The mechanism underlying seizures with cortical malformations is still poorly understood. To study the physiology of dysplastic cortex, we developed an experimental model of CD.


METHODS
Pregnant rats were given intraperitoneal injections of carmustine (1-3-bis-chloroethyl-nitrosourea; BCNU) on embryonic day 15 (E15). Cortical histology was examined in the resulting pups at P0, P28, and P60. In addition, evoked and spontaneous field potential recordings were obtained in cortical slices from adult control and BCNU-exposed rats. Finally, we used whole-cell recordings to compare physiologic properties of pyramidal neurons and gamma-aminobutyric acid (GABA) responses in control and BCNU-treated animals.


RESULTS
Features characteristic of CD were found in the offspring, including laminar disorganization, cytomegalic neurons, and neuronal heterotopias. Dysplastic cortex also contained abnormal clusters of Cajal-Retzius (CR) cells and disruption of radial glial fibers, as demonstrated with immunohistochemistry. Under conditions of partial GABAA-receptor blockade with 10 microM bicuculline methiodide (BMI), slices of dysplastic cortex demonstrated a significant increase in the number of spontaneous and evoked epileptiform discharges. Individual pyramidal neurons in dysplastic cortex were less sensitive to application of GABA compared with controls.


CONCLUSIONS
BCNU exposure in utero produces histologic alterations suggestive of CD in rat offspring. Dysplastic cortex from this model demonstrates features of hyperexcitability and decreased neuronal sensitivity to GABA. Such physiologic alterations may underlie the increased epileptogenicity of dysplastic cortex.
Benardete
Ethan A
EA
Department of Neurology and Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons; and Department of Neurosurgery, NYU Medical Center, New York, New York 10032, USA.
Kriegstein
Arnold R
AR
D000818:Animals; D001640:Bicuculline / Q000031:analogs & derivatives* / Q000494:pharmacology; D002330:Carmustine / Q000494:pharmacology; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000187:drug effects* / Q000503:physiopathology; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004594:Electrophysiology; D004827:Epilepsy / Q000503:physiopathology*; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D007150:Immunohistochemistry; D008098:Litter Size / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D011247:Pregnancy; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D018079:Receptors, GABA / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology* / Q000502:physiology
D018079:Receptors, GABA; C017069:bicuculline methiodide; D005680:gamma-Aminobutyric Acid; D002330:Carmustine; D001640:Bicuculline