Neurons Recorded from Pediatric Epilepsy Surgery Patients with Cortical Dysplasia (original) (raw)
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Journal of Neuroscience Research, 2003
The mechanisms responsible for seizure generation in cortical dysplasia (CD) are unknown, but morphologically abnormal cells could contribute. We examined the passive and active membrane properties of cells from pediatric CD in vitro. Normal-and abnormal-appearing cells were identified morphologically by using infrared videomicroscopy and biocytin in slices from children with mild to severe CD. Electrophysiological properties were assessed with patch clamp recordings. Four groups of abnormal-appearing cells were observed. The first consisted of large, pyramidal cells probably corresponding to cytomegalic neurons. Under conditions that reduced the contribution of K ϩ conductances, these cells generated large Ca 2ϩ currents and influx when depolarized. When these cells were acutely dissociated, peak Ca 2ϩ currents and densities were greater in cytomegalic compared with normal-appearing pyramidal neurons. The second group included large, nonpyramidal cells with atypical somatodendritic morphology that could correspond to "balloon" cells. These cells did not display active voltage-or ligand-gated currents and did not appear to receive synaptic inputs. The third group included misoriented and dysmorphic pyramidal neurons, and the fourth group consisted of immaturelooking pyramidal neurons. Electrophysiologically, neurons in these latter two groups did not display significant abnormalities when compared with normalappearing pyramidal neurons. We conclude that there are cells with abnormal intrinsic membrane properties in pediatric CD. Among the four groups of cells, the most abnormal electrophysiological properties were displayed by cytomegalic neurons and large cells with atypical morphology. Cytomegalic neurons could play an important role in the generation of epileptic activity.
Basic Mechanisms of Epileptogenesis in Pediatric Cortical Dysplasia
CNS Neuroscience & Therapeutics, 2014
Cortical dysplasia (CD) is a neurodevelopmental disorder due to aberrant cell proliferation and differentiation. Advances in neuroimaging have proven effective in early identification of the more severe lesions and timely surgical removal to treat epilepsy. However, the exact mechanisms of epileptogenesis are not well understood. This review examines possible mechanisms based on anatomical and electrophysiological studies. CD can be classified as CD type I consisting of architectural abnormalities, CD type II with the presence of dysmorphic cytomegalic neurons and balloon cells, and CD type III which occurs in association with other pathologies. Use of freshly resected brain tissue has allowed a better understanding of basic mechanisms of epileptogenesis and has delineated the role of abnormal cells and synaptic activity. In CD type II, it was demonstrated that balloon cells do not initiate epileptic activity, whereas dysmorphic cytomegalic and immature neurons play an important role in generation and propagation of epileptic discharges. An unexpected finding in pediatric CD was that GABA synaptic activity is not reduced, and in fact, it may facilitate the occurrence of epileptic activity. This could be because neuronal circuits display morphological and functional signs of dysmaturity. In consequence, drugs that increase GABA function may prove ineffective in pediatric CD. In contrast, drugs that counteract depolarizing actions of GABA or drugs that inhibit the mammalian target of rapamycin (mTOR) pathway could be more effective.
Journal of Neuroscience Methods, 1995
The recent emergence of surgical treatment of childhood epilepsy has led to the accessibility of young human cerebral tissue for electrophysiological studies of the mechanisms involved in epileptogenesis. Intracellular recordings were obtained from neurons in slices prepared from neocortical tissue resected from children (3 months to 15 years) with catastrophic epilepsy. Data from ‘least abnormal’ versus ‘most abnormal’ tissue were compared; the evaluation of the degree of abnormality was based on several clinical criteria. Hypotheses concerning NMDA receptors, local synaptic circuits, and epileptiform bursts were tested. The NMDA receptor-mediated component of synaptic responses, which was isolated pharmacologically, had a voltage dependence that was functionally mature by 8-10 months of age and did not appear to be altered even in the most abnormal tissue. Local inhibitory and excitatory synaptic circuits were present as early as 11 months and 8 months, respectively. Local excitatory circuits were sufficiently extensive in young children to initiate and sustain epileptiform activity when synaptic inhibition was suppressed. Bicuculline-induced epileptiform bursts were similar to those in adult human or animal neocortical slices.Burst duration and the presence of after-discharges were unrelated to patient age or tissue abnormality. These data demonstrated that (1) the electrophysiological properties of human neocortical neurons are very similar to those observed in animal experiments, (2) the mechanisms of neuronal communication are qualitatively mature within the first year of life, and (3) synaptic transmission and local neuronal circuits appear qualitatively normal, even in the most abnormal tissue from children with catastrophic epilepsy.
Epileptogenesis in pediatric cortical dysplasia: The dysmature cerebral developmental hypothesis
Epilepsy & Behavior, 2006
Cortical dysplasia (CD) is the most frequent pathology found in pediatric epilepsy surgery patients with a nearly 80% incidence in children younger than 3 years of age. Younger cases are more likely to have multilobar and severe forms of CD compared with older patients with focal and mild CD. Using clinico-pathologic techniques, we have initiated studies that unravel the timing of CD pathogenesis that in turn suggest mechanisms of epileptogenesis. Morphological comparisons provided the first clue when we observed that cytomegalic neurons have similarities with human subplate cells, and balloon cells have features analogous to radial glia. This suggested that failure of prenatal cell degeneration before birth could explain the presence of postnatal dysmorphic cells in CD tissue. Neuronal density and MRI volumes indicate that there were more neurons than expected in CD tissue, and they were probably produced in later neurogenesis cell cycles. Together these findings imply that there is partial failure in later phases of cortical development that might explain the distinctive histopathology of CD. If correct, epileptogenesis should be the consequence of incomplete cellular maturation in CD tissue. In vitro electrophysiological findings are consistent with this notion. They show that balloon cells have glial features, cytomegalic neurons and recently discovered cytomegalic interneurons reveal atypical hyperexcitable intrinsic membrane properties, there are more GABA than glutamate spontaneous synaptic inputs onto neurons, and in a subset of cells NMDA and GABA A receptor-mediated responses and subunit expression are similar to those of immature neurons. Our studies support the hypothesis that there are retained prenatal cells and neurons with immature cellular and synaptic properties in pediatric CD tissue. We propose that local interactions of dysmature cells with normal postnatal neurons produce seizures. This hypothesis will drive future studies aimed at elucidating mechanisms of epileptogenesis in pediatric CD tissue.
Developmental Neuroscience, 2005
Seizures in cortical dysplasia (CD) could be from cytomegalic neurons and balloon cells acting as epileptic 'pacemakers', or abnormal neurotransmission. This study examined these hypotheses using in vitro electrophysiological techniques to determine intrinsic membrane properties and spontaneous glutamatergic and GABAergic synaptic activity for normal-pyramidal neurons, cytomegalic neurons and balloon cells from 67 neocortical sites originating from 43 CD patients (ages 0.2-14 years). Magnetic resonance imaging (MRI), 18 fluoro-2-deoxyglucose positron emission tomography (FDG-PET) and electrocorticography graded cortical sample sites from least to worst CD abnormality. Results found that cytomegalic neurons and balloon cells were observed more frequently in areas of severe CD compared with mild or normal CD regions as assessed by FDG-PET/MRI. Cytomegalic neurons (but not balloon cells) correlated with the worst electrocorticography scores. Electrophysiological recordings demonstrated that cytomegalic and normalpyramidal neurons displayed similar firing properties without intrinsic bursting. By contrast, balloon cells were electrically silent. Normal-pyramidal and cytomegalic neurons displayed decreased spontaneous glutamatergic synaptic activity in areas of severe FDG-PET/MRI abnormalities compared with normal regions, while GABAergic activity was unaltered. In CD, these findings indicate that cytomegalic neurons (but not balloon cells) might contribute to epileptogenesis, but are not likely to be 'pacemaker' cells capable of spontaneous paroxysmal depolarizations. Furthermore, there was more GABA relative to glutamate synaptic neurotransmission in areas of severe CD. Thus, in CD tissue alternate mechanisms of epileptogenesis should be considered, and we suggest that GABAergic synaptic circuits interacting with cytomegalic and normal-pyramidal neurons with immature receptor properties might contribute to seizure generation.
Rational: Cortical dysplasia has been associated with intractable epilepsy by many clinical studies. Animal model of cortical dysplasia using cortical freeze lesion in early development stage mimic the microgyra described in human. Methods: Cortical freeze lesion was performed in anesthe-tised new born rat at postnatal day 1. Whole cell current clamp recordings were used to investigate the changes in electrophysiological properties of CA1 pyramidal cells in this model. Results: The membrane potential and input resistance of CA1 pyramidal cells were not affected in this model. However the action potential threshold was lowered in lesion group and accompanied by an increase in the firing frequency in response to depolarising currents. In addition, the amplitude of spike afterhyperpolarisations was significantly decreased in lesion group. Conclusion: The increase excitability of CA1 pyramidal cells in cortical freeze lesion may increase the likelihood to develop epilepsy at adulthood.
Journal of Clinical Neurophysiology, 2010
To test the hypothesis that focal and parafocal neocortical tissue from pediatric patients with intractable epilepsy exhibits cellular and synaptic differences, the authors characterized the propensity of these neurons to generate (a) voltage-dependent bursting and (b) synaptically driven paroxysmal depolarization shifts. Neocortical slices were prepared from tissue resected from patients with intractable epilepsy. Multiunit network activity and simultaneous whole-cell patch recordings were made from neurons from three patient groups: (1) those with normal histology; (2) those with mild and severe cortical dysplasia; and (3) those with abnormal pathology but without cortical dysplasia. Seizure-like activity was characterized by population bursting with concomitant bursting in intracellularly recorded cortical neurons (n = 59). The authors found significantly more N-methyl-D-aspartic acid-driven voltage-dependent bursting neurons in focal versus parafocal tissue in patients with severe cortical dysplasia (P < 0.01). Occurrence of paroxysmal depolarization shifts and burst amplitude and burst duration were significantly related to tissue type: focal or parafocal (P < 0.05). The authors show that functional differences between focal and parafocal tissue in patients with severe cortical dysplasia exist. There are functional differences between patient groups with different histology, and bursting properties can be significantly associated with the distinction between focal and parafocal tissue.
Immature Neurons and GABA Networks May Contribute to Epileptogenesis in Pediatric Cortical Dysplasia
Epilepsia, 2007
Cortical dysplasia (CD), a frequent pathological substrate of pediatric epilepsy surgery patients, has a number of similarities with immature cortex, such as reduced Mg 2+ sensitivity of N-methyl-D-aspartate (NMDA) receptors and the persistence of subplate-like neurons and undifferentiated cells. Because γ -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 Address correspondence and reprint requests to Carlos Cepeda, Ph.D., MRRC, NPI room 58-258,
Epileptogenesis and Cortical Dysplasias
Springer eBooks, 2010
Cortical dysplasia (CD) is a malformation of brain development characterized by aberrant lamination of the cerebral cortex, pyramidal cell misorientation, and in severe cases, the presence of dysplastic cytomegalic neurons and balloon cells (Taylor et al. 1971). In children undergoing epilepsy neurosurgery, CD is the most frequently identified etiology accounting for over 40% of cases (Harvey et al. 2008). In fact, CD is found in approximately 70% of epilepsy surgery patients operated in the first 2 years of life. C.P. Panayiotopoulos (ed.