title: Immature neurons and GABA networks may contribute to epileptogenesis in pediatric cortical dysplasia.
abstract: Cortical dysplasia (CD), a frequent pathological substrate of pediatric epilepsy surgery patients, has a number of similarities with immature cortex, such as reduced Mg2+ sensitivity of N-methyl-D-aspartate (NMDA) receptors and the persistence of subplate-like neurons and undifferentiated cells. Because gamma-aminobutyric acid (GABA) is the main neurotransmitter in early cortical development, we hypothesized increased GABA receptor-mediated synaptic function in CD tissue. Infrared videomicroscopy and whole-cell patch clamp recordings were used to characterize the morphology and electrophysiological properties of immature and normal-appearing neurons in slices from cortical tissue samples resected for the treatment of pharmacoresistant epilepsy in children (0.2-14 years). In addition, we examined spontaneous and evoked synaptic activity, as well as responses to exogenous GABA application. We demonstrate both the presence of immature pyramidal neurons and networks in young CD tissue and the predominance of GABA synaptic activity. In addition, spontaneous GABA depolarizations frequently induced action potentials, supporting a potential excitatory role of GABA in CD. Evoked synaptic responses mediated by GABA were also prominent, and bath application of 4-aminopyridine induced rhythmic depolarizations that were blocked by bicuculline. Finally, responses to exogenous application of GABA had depolarized reversal potentials in severe compared to mild and non-CD cases. The present data support the hypothesis that CD shares features of immature cortex, with predominant and potentially excitatory GABA(A) receptor-mediated neurotransmission. These results could partially explain the increased excitability of the cortical network in pediatric CD.
authors.affiliation: Mental Retardation Research Center, David Geffen School of Medicine, University of California, Los Angeles, California 90024, USA. ccepeda@mednet.ucla.edu
authors.forename: Carlos
authors.initials: C
authors.lastname: Cepeda
authors.forename: Véronique M
authors.initials: VM
authors.lastname: André
authors.forename: Nanping
authors.initials: N
authors.lastname: Wu
authors.forename: Irene
authors.initials: I
authors.lastname: Yamazaki
authors.forename: Besim
authors.initials: B
authors.lastname: Uzgil
authors.forename: Harry V
authors.initials: HV
authors.lastname: Vinters
authors.forename: Michael S
authors.initials: MS
authors.lastname: Levine
authors.forename: Gary W
authors.initials: GW
authors.lastname: Mathern
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000293:Adolescent; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000187:drug effects / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D004594:Electrophysiology; D004827:Epilepsy / Q000473:pathology* / Q000503:physiopathology; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007223:Infant; D007478:Iontophoresis / Q000379:methods; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid