Immature Neurons and GABA Networks May Contribute to Epileptogenesis in Pediatric Cortical Dysplasia

Mental Retardation Research Center, David Geffen School of Medicine, University of California, Los Angeles, California 90024, USA.
Epilepsia (Impact Factor: 4.57). 02/2007; 48 Suppl 5(s5):79-85. DOI: 10.1111/j.1528-1167.2007.01293.x
Source: PubMed


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.

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Available from: Carlos Cepeda, Oct 13, 2014
    • "This assumption is supported by a report on changes in the expression of the chloride transporters KCC2 and NKCC1 in neocortical tissue resected in children with intractable focal epilepsy using quantitative western blot analyses (Jansen et al., 2010). A significant decrease in the mRNA and protein levels of the chloride outward transporter KCC2 has been demonstrated in human dysplastic tissue (Shimizu-Okabe et al., 2011), indicating that the chloride reversal potential is more depolarized, as reported by Cepeda et al. (2007). Finally, beside deficits in glutamatergic and GABAergic synaptic function contributing to the epileptogenicity of cortical malformations, abnormal intrinsic membrane properties have been also reported dysplastic cortex (Cepeda et al., 2003). "
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    ABSTRACT: Pharmaco-resistant epilepsies, and also some neuropsychiatric disorders, are often associated with malformations in hippocampal and neocortical structures. The mechanisms leading to these cortical malformations causing an imbalance between the excitatory and inhibitory system are largely unknown. Animal models using chemical or physical manipulations reproduce different human pathologies by interfering with cell generation and neuronal migration. The model of in utero injection of methylazoxymethanol (MAM) acetate mimics periventricular nodular heterotopia. The freeze lesion model reproduces (poly)microgyria, focal heterotopia and schizencephaly. The in utero irradiation model causes microgyria and heterotopia. Intraperitoneal injections of carmustine 1-3-bis-chloroethyl-nitrosurea (BCNU) to pregnant rats produces laminar disorganization, heterotopias and cytomegalic neurons. The ibotenic acid model induces focal cortical malformations, which resemble human microgyria and ulegyria. Cortical dysplasia can be also observed following prenatal exposure to ethanol, cocaine or antiepileptic drugs. All these models of cortical malformations are characterized by a pronounced hyperexcitability, few of them also produce spontaneous epileptic seizures. This dysfunction results from an impairment in GABAergic inhibition and/or an increase in glutamatergic synaptic transmission. The cortical region initiating or contributing to this hyperexcitability may not necessarily correspond to the site of the focal malformation. In some models wide-spread molecular and functional changes can be observed in remote regions of the brain, where they cause pathophysiological activities. This paper gives a overview on different animal models of cortical malformations, which are mostly used in rodents and which mimic the pathology and to some extent the pathophysiology of neuronal migration disorders associated with epilepsy in humans. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Apr 2015 · Journal of Neuroscience Methods
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    • "Many reports indicate that seizures may alter GABA A R signaling in immature and mature periods. Following the report of depolarizing GABA A R responses in human epileptic subiculum (Cohen et al., 2002), multiple studies confirmed or extended these findings that suggest abnormal CCC expression and depolarizing GABA A R in human epileptic tissues (Aronica et al., 2007; Cepeda et al., 2007; Conti et al., 2011; Huberfeld et al., 2007; Jansen et al., 2010; Munakata et al., 2007; Munoz et al., 2007; Palma et al., 2006; Talos et al., 2012a). Several animal studies also indicated that seizures or the epileptic state in adult rodents may lead to re-appearance of depolarizing GABA A R due to either increase in NKCC1 or decrease in KCC2 activity (Benini and Avoli, 2006; Okabe et al., 2002,c 2003; Pathak et al., 2007; Rivera et al., 2002). "
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    ABSTRACT: Seizures are very common in the early periods of life and are often associated with poor neurologic outcome in humans. Animal studies have provided evidence that early life seizures may disrupt neuronal differentiation and connectivity, signaling pathways, and the function of various neuronal networks. There is growing experimental evidence that many signaling pathways, like GABAA receptor signaling, the cellular physiology and differentiation, or the functional maturation of certain brain regions, including those involved in seizure control, mature differently in males and females. However, most experimental studies of early life seizures have not directly investigated the importance of sex on the consequences of early life seizures. The sexual dimorphism of the developing brain raises the question that early seizures could have distinct effects in immature females and males that are subjected to seizures. We will first discuss the evidence for sex-specific features of the developing brain that could be involved in modifying the susceptibility and consequences of early life seizures. We will then review how sex-related biological factors could modify the age-specific consequences of induced seizures in the immature animals. These include signaling pathways (e.g., GABAA receptors), steroid hormones, growth factors. Overall, there are very few studies that have specifically addressed seizure outcomes in developing animals as a function of sex. The available literature indicates that a variety of outcomes (histopathological, behavioral, molecular, epileptogenesis) may be affected in a sex-, age-, region- specific manner after seizures during development. Obtaining a better understanding for the gender-related mechanisms underlying epileptogenesis and seizure comorbidities will be necessary to develop better gender and age appropriate therapies.
    Full-text · Article · May 2014 · Neurobiology of Disease
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    • "GABAergic interneurons are hypothesized to play a crucial role in epileptogenesis (Cepeda et al. 2007; Cossart et al. 2005; Magloczky and Freund 2005). In addition, interneurons are important for synchronizing populations of excitatory neurons (Cobb et al. 1995; Somogyi et al. 1998) and activation of inhibitory neurons can drive hippocampal seizurelike activity (Fujiwara-Tsukamoto et al. 2010). "
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    ABSTRACT: Hyperpolarization-activated, cyclic-nucleotide gated, non-specific cation (HCN) channels have a well-characterized role in regulation of cellular excitability and network activity. The role of these channels in control of epileptiform discharges is less thoroughly understood. This is especially pertinent given altered HCN channel expression in epilepsy. We hypothesized that inhibition of HCN channels would enhance bicuculline-induced epileptiform discharges. Whole-cell recordings were obtained from layers 2/3 and 5 (L2/3; L5) pyramidal neurons and L1 and L5 GABAergic interneurons. In the presence of bicuculline (10 uM), HCN channel inhibition with ZD7288 (20 uM) significantly increased the magnitude (defined as area) of evoked epileptiform events in both L2/3 and L5 neurons. We recorded activity associated with epileptiform discharges in L1 and L5 interneurons to test the hypothesis that HCN channels regulate excitatory synaptic inputs differently in interneurons versus pyramidal neurons. HCN channel inhibition increased the magnitude of epileptiform events in both L1 and L5 interneurons. The increased magnitude of epileptiform events in both pyramidal cells and interneurons was due to an increase in network activity since holding cells at depolarized potentials under voltage-clamp conditions to minimize HCN channel opening did not prevent enhancement in the presence of ZD7288. In neurons recorded with ZD7288-containing pipettes, bath application of the Ih antagonist still produced increases in epileptiform responses. These results show that epileptiform discharges in disinhibited rat neocortex are modulated by HCN channels.
    Full-text · Article · Jul 2013 · Journal of Neurophysiology
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