title: Status epilepticus-induced pathologic plasticity in a rat model of focal cortical dysplasia.
abstract: We have generated an experimental 'double-hit' model of chronic epilepsy to recapitulate the co-existence of abnormal cortical structure and frequently recurrent seizures as observed in human focal cortical dysplasia. We induced cortical malformations by exposing rats prenatally to methylazoxymethanol acetate and triggered status epilepticus and recurrent seizures in adult methylazoxymethanol acetate rats with pilocarpine. We studied the course of epilepsy and the long-term morphologic and molecular changes induced by the occurrence of status epilepticus and subsequent chronic epilepsy in the malformed methylazoxymethanol acetate exposed brain. Behavioural and electroencephalographic analyses showed that methylazoxymethanol acetate pilocarpine rats develop more severe epilepsy than naïve rats. Morphologic and molecular analyses demonstrated that status epilepticus and subsequent seizures, but not pilocarpine treatment per se, was capable of affecting both cortical architectural and N-methyl-D-aspartate receptor abnormalities induced by methylazoxymethanol acetate. In particular, cortical thickness was further decreased and N-methyl-D-aspartate regulatory subunits were recruited at the postsynaptic membrane. In addition, methylazoxymethanol acetate pilocarpine rats showed abnormally large cortical pyramidal neurons with neurofilament over-expression. These neurons bear similarities to the hypertrophic/dysmorphic pyramidal neurons observed in acquired human focal cortical dysplasia. These data show that status epilepticus sets in motion a pathological process capable of significantly changing the cellular and molecular features of pre-existing experimental cortical malformations. They suggest that seizure recurrence in human focal cortical dysplasia might be an additional factor in establishing a pathological circuitry that favours chronic neuronal hyperexcitability.
authors.affiliation: Molecular Neuroanatomy and Pathogenesis Unit, Neurological Institute C. Besta, via Temolo 4, 20126 Milano, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Colciaghi
authors.forename: Adele
authors.initials: A
authors.lastname: Finardi
authors.forename: Angelisa
authors.initials: A
authors.lastname: Frasca
authors.forename: Silvia
authors.initials: S
authors.lastname: Balosso
authors.forename: Paola
authors.initials: P
authors.lastname: Nobili
authors.forename: Giovanni
authors.initials: G
authors.lastname: Carriero
authors.forename: Denise
authors.initials: D
authors.lastname: Locatelli
authors.forename: Annamaria
authors.initials: A
authors.lastname: Vezzani
authors.forename: Giorgio
authors.initials: G
authors.lastname: Battaglia
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D054220:Malformations of Cortical Development / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D008746:Methylazoxymethanol Acetate; D009474:Neurons / Q000473:pathology* / Q000502:physiology; D010862:Pilocarpine; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D013226:Status Epilepticus / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology
chemical_list: D010862:Pilocarpine; D008746:Methylazoxymethanol Acetate