Neurons Recorded from Pediatric Epilepsy Surgery Patients with Cortical Dysplasia

Abstract

Summary:Purpose: Cortical dysplasia (CD) is a common pathological substrate in patients with early-onset childhood epilepsy. In CD tissue, little is known about the mechanisms responsible for cellular hyperexcitability. In this study, we report initial electrophysiological and morphological observations from normal and dysmorphic cells in pediatric CD patients.Methods: Neocortical "most" and "least" epileptogenic areas were sampled based on neuroimaging and electrocorticography from 15 CD patients (ages 0.3 to 14 years). Whole-cell voltage clamp recordings combined with infrared videomicroscopy sampled abnormal cells (cytomegalic neurons, cells with bifurcated dendrites, disoriented pyramidal cells, etc.) compared with normal-appearing neurons from the same patient. Cells were filled with biocytin, and adjacent tissue blocks were stained for neuronal and glial markers.Results: About 15% of the 161 recorded cells were abnormal in appearance. Abnormal cells showed electrophysiological irregularities ranging from intrinsic cellular hyperexcitability to hyposensitivity after application of ionotropic receptor agonists. Other findings included increased excitatory postsynaptic currents and alterations in y-aminobutyric acid reversal potentials.Conclusions: In pediatric CD tissue, these preliminary results indicate that abnormal-appearing cells showed abnormalities in electrophysiological measures compared with normalappearing neurons. The abnormalities varied from hyperexcitability to hypoexcitability. More detailed results and conclusions will be forthcoming as additional patient material is analyzed.

Pediatric Cortical Dysplasia: Correlations between Neuroimaging, Electrophysiology and Location of Cytomegalic Neurons and Balloon Cells and Glutamate/GABA Synaptic Circuits

“…Recent studies from our laboratory using in vitro cellular electrophysiologic and anatomic techniques have provided support for both the 'epileptic' neuron and circuit hypotheses in pediatric CD tissue Andres et al, 2004;Cepeda et al, 1999Cepeda et al, , 2003Mathern et al, 2000]. Using voltage-clamp recording techniques, we found that when cytomegalic neurons were depolarized they generated large oscillatory voltage-gated calcium spikes.…”

Malformations of cortical development: current concepts and advanced neuroimaging review

“…Evidences from in vitro studies show that cytomegalic neurons are primary epileptogenic cells, whereas "balloon" cells are electrophysiologically inactive 38,43 . FCD are probably not a single entity.…”

Cytomegalic Interneurons

“…Six cytomegalic interneurons were aspiny or sparsely spiny and 2 were spiny. The number of primary dendrites (8,9) in cytomegalic interneurons was significantly increased compared with that in normal interneurons from non-CD (p G 0.006) and CD (p G 0.033) cases (ANOVA, followed by Bonferroni t-test). Dendritic spines (average 13 T 3/30 Km) were more abundant than in normalappearing interneurons (8 T 2 spines), but the difference was not statistically significant (p = 0.8).…”

“…Neocortical sample sites were removed for in vitro electrophysiologic and anatomical evaluation based on abnormal neuroimaging and electrocorticography results as previously described (9,11,13). Tissue samples were classified as most abnormal or least abnormal, and, when possible, 2 sample sites were obtained from each patient (7,10).…”

“…Most cytomegalic neurons were pyramidal-shaped cells with abnormal intrinsic membrane properties and signs of hyperexcitability manifested by increased calcium conductances (10), supporting the idea that cytomegalic neurons could contribute to the amplification and spread of epileptic discharges (7, 11Y13). Balloon cells had mostly glial features and were unable to generate inward currents, suggesting a minor role in CD epileptogenesis (7,9,10,13).…”