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.

Progressive Brain Damage, Synaptic Reorganization and NMDA Activation in a Model of Epileptogenic Cortical Dysplasia

“…Altogether this evidence suggests the progressive nature of severe seizures in both experimental models and humans [1]–[2]. In line with this hypothesis, we have very recently demonstrated that epilepsy duration was positively correlated with morphometric changes of both neurons and glia and greater glutamatergic input in the epileptogenic/dysplastic areas of FCD patients [86]. It is possible, therefore, that the progressive pathologic plasticity we describe here might also occur in severe, malformation-related human epilepsies.…”

Gamma‐aminobutyric acidergic transmission underlies interictal epileptogenicity in pediatric focal cortical dysplasia

“…7,[33][34][35] Alteration of the extracellular matrix through increased expression of metalloproteinase 9 leading to putative modified intra-and extracellular chloride levels has been reported. Previous studies reported several possible mechanisms underlying the epileptogenicity in FCD.…”

“…Glutamatergic transmission supports ictogenesis in human FCD slices, 32 due to an increased expression and altered composition of NMDA (NR2B subunit) receptors. 7,[33][34][35] Alteration of the extracellular matrix through increased expression of metalloproteinase 9 leading to putative modified intra-and extracellular chloride levels has been reported. 36 Involvement of purinergic transmission was also proposed, via an excess of adenosine triphosphate release through pannexin 1 channels, 37 although this pathway is not specific to FCD epileptogenesis.…”

Histological Characterization of Inter Ictal Epileptiform Discharges Generating Brain Regions using a Preclinical Model of Focal Cortical Dysplasia

“…We found extensive reactive gliosis (with altered astrocyte morphology) in localized irritative region which corroborates finding that longer chronic epilepsy is associated with more intensive reactive gliosis and astrocyte alterations in epileptogenic region, further evidence that epilepsy is a progressive pathology (Finardi A, et al, 2013). Astrocytes undergo changes in morphology, molecular composition, and proliferation in epileptogenic region.…”