Article

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: 4.58). 02/2007; 48 Suppl 5(s5):79-85. DOI: 10.1111/j.1528-1167.2007.01293.x
Source: PubMed

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.

Download full-text

Full-text

Available from: Carlos Cepeda, Oct 13, 2014
0 Followers
 · 
111 Views
  • Source
    [Show abstract] [Hide abstract]
    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.
    Neurobiology of Disease 05/2014; DOI:10.1016/j.nbd.2014.05.021 · 5.20 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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.
    Journal of Neurophysiology 07/2013; 110(8). DOI:10.1152/jn.00955.2012 · 3.04 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Focal cortical dysplasias (FCDs) are highly epileptogenic malformations associated with drug-resistant epilepsy, susceptible to surgical treatment. Among the different types of FCD, the type II includes two subgroups based on the absence (IIa) or presence (IIb) of balloon cells. The aim of this retrospective study was to investigate possible differences in electroclinical presentations and surgical outcomes between the two subgroups in 100 consecutive surgically treated patients with type II FCDs. All patients underwent a comprehensive presurgical assessment including stereo-EEG (SEEG) when necessary. No significant differences in gender, age at epilepsy onset, duration of epilepsy, age at surgery or seizure frequency were found between the two subgroups. Patients with type IIb FCD frequently showed sleep-related epilepsy. Their peculiar electrographic pattern was characterised by localised rhythmic or pseudo-rhythmic spikes or polyspikes ("brushes") enhanced during non-REM sleep and also associated with well-localised, brief, low-voltage fast activity. The incidence and frequency of short bursts of fast discharges, interrupted by activity suppression, increased during slow-wave sleep and often recurred pseudo-periodically. The occurrence of "brushes", present in 76% of the patients with type IIb FCD, was significantly associated (p<0.001) with the presence of balloon cells. We discuss the possible pathogenetic mechanisms underlying this activity. MRI diagnosis of type II FCD was made in 93% of the patients with balloon cells (BCs), suggesting that the presence of balloon cells might be, at least partially, responsible for the MRI features. Patients had very good postsurgical outcomes (83% in Engel class I) even after a long period of follow-up.
    Epileptic disorders: international epilepsy journal with videotape 09/2012; 14(3):257-66. DOI:10.1684/epd.2012.0525 · 0.90 Impact Factor