Pacemaker GABA synaptic activity may contribute to network synchronization in pediatric cortical dysplasia

doi:10.1016/j.nbd.2013.10.001

Neurobiology of Disease

Volume 62, February 2014, Pages 208-217

https://doi.org/10.1016/j.nbd.2013.10.001 Get rights and content

Highlights

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Pacemaker GABA synaptic activity (PGA) is a hallmark of pediatric cortical dysplasia.
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PGA occurs in areas with greatest anatomical abnormality.
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PGA is abolished by GABA_A receptor antagonists and sodium channel blockers.
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PGA frequency is ~ 7.5 Hz and displays high degree of autocorrelation.
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PGA could represent a signal for network synchronization in dysplastic cortex.

Abstract

Spontaneous pacemaker γ-aminobutyric acid (GABA) receptor-mediated synaptic activity (PGA) occurs in a subset of tissue samples from pediatric epilepsy surgery patients. In the present study, based on single-cell electrophysiological recordings from 120 cases, we describe the etiologies, cell types, and primary electrophysiological features of PGA. Cells displaying PGA occurred more frequently in the areas of greatest anatomical abnormality in cases of focal cortical dysplasia (CD), often associated with hemimegalencephaly (HME), and only rarely in non-CD etiologies. PGA was characterized by rhythmic synaptic events (5–10 Hz) and was observed in normal-like, dysmorphic cytomegalic, and immature pyramidal neurons. PGA was action potential-dependent, mediated by GABA_A receptors, and unaffected by antagonism of glutamate receptors. We propose that PGA is a unique electrophysiological characteristic associated with CD and HME. It could represent an abnormal signal that may contribute to epileptogenesis in malformed postnatal cortex by facilitating pyramidal neuron synchrony.

Introduction

Cortical dysplasia (CD) is a neurodevelopmental disorder characterized by cortical dyslamination and, in severe cases, the presence of aberrant cells including dysmorphic neurons and balloon cells (Taylor et al., 1971). CD is the most common pathological substrate in pediatric epilepsy surgery patients (Harvey et al., 2008, Lerner et al., 2009, Mathern et al., 1999) and seizures are usually refractory to antiepileptic drugs (AEDs) (Barkovich et al., 2012). Tuberous sclerosis complex (TSC), a genetic autosomal dominant disorder characterized by cortical and subcortical tubers, displays similar histopathologic features as severe CD, and also presents with a high incidence of epilepsy.

Previous studies have characterized some of the morphological, electrophysiological, and molecular biological features of abnormal cells in CD and TSC (Cepeda et al., 2003, Crino, 2010). For example, our group demonstrated that balloon cells are unable to generate epileptic discharges due to the lack of ionic conductances required for the generation of action potentials and do not receive synaptic inputs (Cepeda et al., 2005b). In contrast, dysmorphic cytomegalic pyramidal neurons display increased Ca^2 + conductances and reduced Mg^2 + sensitivity, suggesting that they have a role in epileptogenesis (Andre et al., 2004, Andre et al., 2007, Cepeda et al., 2003, Cepeda et al., 2005a, Cepeda et al., 2005b, Cepeda et al., 2006, Cepeda et al., 2007, Mathern et al., 2000). We also demonstrated that the frequency of spontaneous GABA_A receptor-mediated synaptic activity, relative to glutamate receptor-mediated synaptic activity, is increased in CD compared with non-CD cases (Cepeda et al., 2005a). This led us to propose a developmental dysmaturity hypothesis of epileptogenesis in CD (Cepeda et al., 2006).

Other findings from our investigations have shown that CD tissue contains elements of abnormal neuronal maturation. For example, CD cases often contain clusters of immature pyramidal neurons showing signs of increased membrane excitability (Cepeda et al., 2007). In a subpopulation of immature pyramidal neurons we observed the occurrence of spontaneous, rhythmic GABAergic synaptic events (Cepeda et al., 2003). As rhythmic activity could promote epileptogenesis by contributing to network synchronization, the present study was designed to further investigate the incidence and principal characteristics of pacemaker GABA synaptic activity (PGA) in pediatric epilepsy surgery cases.

Section snippets

Methods

The research protocols were approved by the Institutional Review Board of the Human Protection Research Committee at the University of California Los Angeles (UCLA). Informed consent to use the surgically resected tissue for research was obtained from the parents or legal guardians. This study is not a clinical trial and it is not recorded in any public registry.

PGA occurs in the most abnormal regions of CD and HME cases

In the cohort that met our inclusion criteria (n = 120 cases, average age 3.8 ± 0.3 yr, range 0.2–14.2 yr), cells displaying PGA were mostly found in patients with CD. An example of ECoG, MRI, and histopathology from a CD Type IIb case (3.6 yr) that displayed PGA at the cellular level is illustrated in Fig. 1 (A–C). In patients with CD, 27 of 80 (34%) cases displayed PGA (Table 1). In contrast, only 2 of 25 non-CD cases displayed PGA (8%; p = 0.01, Chi-square). As might be expected from previous reports

Discussion

The present study provides a characterization of neurons that display PGA from pediatric epilepsy surgery patients. Cells displaying PGA occurred more frequently in cases of CD compared with non-CD etiologies, and were more related to histopathology rather than the younger age at surgery. For CD cases, within subject comparisons demonstrated that the majority of cells displaying PGA occurred in the MA cortical samples. PGA was characterized by rhythmic, clock-like events (5–10 Hz), was action

Acknowledgments

The authors would like to thank the patients and their parents for allowing the use of resected specimens for experimentation. We also thank the UCLA Hospital Pediatric Neurology staff for their assistance. Drs. Jorge Flores-Hernández, Gloria J. Klapstein, Raymond S. Hurst, Max Kleiman-Weiner, Irene Yamazaki, Besim Uzgil and Galatia J. Cepeda participated in data collection and analysis. My N. Huynh did the biocytin processing and Donna Crandall helped with the illustrations. This work was

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While the most accepted canon is that FRs emerge from synchronous activation of CPNs, we hypothesize that FSIs could directly contribute to pathological FR generation. We also demonstrated that FR areas not only correlate with high GABA synaptic activity but also with the PGA we described several years ago (Cepeda et al., 2014). This is significant because EEG studies in FCD have shown that rhythmic epileptic discharges (REDs) associate with the structural abnormalities in the epileptogenic region and we showed that PGA could in fact underlie REDs (Cepeda et al., 2014; Chassoux et al., 2000; Gambardella et al., 1996).
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Pacemaker GABA synaptic activity may contribute to network synchronization in pediatric cortical dysplasia

Highlights

Abstract

Introduction

Section snippets

Methods

PGA occurs in the most abnormal regions of CD and HME cases

Discussion

Acknowledgments

Epilepsy Behav.

Neurobiol. Dis.

Electroencephalogr. Clin. Neurophysiol.

Neurosci. Lett.

Neuroscience

Trends Neurosci.

Local Cortical Circuits: An Electrophysiological Study

Mechanisms of spontaneous miniature activity at CA3-CA1 synapses: evidence for a divergence from a random Poisson process

Biol. Bull.

NMDA receptor alterations in neurons from pediatric cortical dysplasia tissue

Cereb. Cortex

Cytomegalic interneurons: a new abnormal cell type in severe pediatric cortical dysplasia

J. Neuropathol. Exp. Neurol.

A developmental and genetic classification for malformations of cortical development: update 2012

Brain

GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations

Physiol. Rev.

The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission

Epilepsia

Morphological and electrophysiological characterization of abnormal cell types in pediatric cortical dysplasia

J. Neurosci. Res.

Pediatric cortical dysplasia: correlations between neuroimaging, electrophysiology and location of cytomegalic neurons and balloon cells and glutamate/GABA synaptic circuits

Dev. Neurosci.

Are cytomegalic neurons and balloon cells generators of epileptic activity in pediatric cortical dysplasia?

Epilepsia