title: Long-duration epilepsy affects cell morphology and glutamatergic synapses in type IIB focal cortical dysplasia.
abstract: To investigate hypothesized effects of severe epilepsy on malformed cortex, we analyzed surgical samples from eight patients with type IIB focal cortical dysplasia (FCD) in comparison with samples from nine non-dysplastic controls. We investigated, using stereological quantification methods, where appropriate, dysplastic neurons, neuronal density, balloon cells, glia, glutamatergic synaptic input, and the expression of N-methyl-D-aspartate (NMDA) receptor subunits and associated membrane-associated guanylate kinase (MAGUK). In all FCD patients, the dysplastic areas giving rise to epileptic discharges were characterized by larger dysmorphic neurons, reduced neuronal density, and increased glutamatergic inputs, compared to adjacent areas with normal cytology. The duration of epilepsy was found to correlate directly (a) with dysmorphic neuron size, (b) reduced neuronal cell density, and (c) extent of reactive gliosis in epileptogenic/dysplastic areas. Consistent with increased glutamatergic input, western blot revealed that NMDA regulatory subunits and related MAGUK proteins were up-regulated in epileptogenic/dysplastic areas of all FCD patients examined. Taken together, these results support the hypothesis that epilepsy itself alters morphology-and probably also function-in the malformed epileptic brain. They also suggest that glutamate/NMDA/MAGUK dysregulation might be the intracellular trigger that modifies brain morphology and induces cell death.
authors.affiliation: Experimental Neurophysiology and Epileptology Department, Molecular Neuroanatomy and Pathogenesis Unit, Neurological Institute C. Besta, Via Temolo 4, 20126, Milan, Italy.
authors.forename: Adele
authors.initials: A
authors.lastname: Finardi
authors.forename: Francesca
authors.initials: F
authors.lastname: Colciaghi
authors.forename: Laura
authors.initials: L
authors.lastname: Castana
authors.forename: Denise
authors.initials: D
authors.lastname: Locatelli
authors.forename: Carlo Efisio
authors.initials: CE
authors.lastname: Marras
authors.forename: Paola
authors.initials: P
authors.lastname: Nobili
authors.forename: Maddalena
authors.initials: M
authors.lastname: Fratelli
authors.forename: Manuela Adele
authors.initials: MA
authors.lastname: Bramerio
authors.forename: Giorgio
authors.initials: G
authors.lastname: Lorusso
authors.forename: Giorgio Stefano
authors.initials: GS
authors.lastname: Battaglia
mesh_terms: D000293:Adolescent; D000328:Adult; D001927:Brain Diseases / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D048429:Cell Size; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D005911:Gliosis / Q000473:pathology / Q000503:physiopathology; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008297:Male; D054220:Malformations of Cortical Development / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D065703:Malformations of Cortical Development, Group I; D008875:Middle Aged; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000473:pathology* / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D055815:Young Adult
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; C493464:SLC17A7 protein, human; D050598:Vesicular Glutamate Transport Protein 1; D018698:Glutamic Acid