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

Cepeda, Carlos; Hurst, Raymond S; Flores‐Hernández, Jorge; Hernández‐Echeagaray, Elizabeth; Klapstein, Gloria J.; Boylan, M.K.; Calvert, C. R.; Jocoy, Emily L.; Nguyen, Oanh Kieu; André, Véronique; Vinters, Harry V.; Ariano, Marjorie A.; Levine, Michael S.; Mathern, Gary W.

doi:10.1002/jnr.10604

Cited by 181 publications

(204 citation statements)

References 53 publications

(69 reference statements)

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“…More o v e r, e l e c t rophysiological re c o rdings "in vitro" of dysplastic tissue from epileptic patients demonstrated that calcium currents and densities are greater in abnormal ("giant") compared with normal-appearing pyramidal neurons. These data support the idea that a b n o rmal or dysplastic neurons could play a role in the generation of epileptic activity in our patient 21 .…”

Section: Discussionsupporting

confidence: 91%

Neurocysticercosis and microscopic hippocampal dysplasia in a patient with refractory mesial temporal lobe epilepsy

Silva

Martins

Marques

et al. 2006

Arq. Neuro-Psiquiatr.

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Médico, Doutorando do Depart a m e n t o de Neurologia e Neuro c i ru rgia da UNIFESP-EPM;7 D o u t o r, Professor do Departamento de Patologia da UNIFESP-EPM; 8 D o u t o r, P rofessor do Departamento de Neurologia e Neuro c i ru rgia da UNIFESP-EPM. This work was supported by FA P E S P, CNPq and CAPES from Brazil. Dr. Alexandre Valotta da Silva received a postdoctoral grant from FAPESP (2003/01195-8 ABSTRACT -Epidemiologic studies suggest that neuro c y s t i c e rcosis (NC) is the main cause of symptomatic epilepsy in developing countries. The association between NC and mesial temporal lobe epilepsy (MTLE) has been re p o rted by several authors. Recent data have shown that the presence of NC does not influence the clinical and pathological profile in MTLE patients and suggest that not all cysticercotic lesions are inevitably epileptogenic. We describe a 50-years-old woman with partial seizures due to NC which evolve to MTLE. The patient was submitted to a corticoamygdalohippocampectomy to treat re f r a c t o ry epilepsy. An immunohistochemical study using neuronal markers was made on hippocampal formation. Besides the typical aspects of Ammon's horn sclerosis (AHS), the microscopic examination demonstrates cellular feat u res of hippocampal malformation including dysmorphic neurons and focal bilamination of granular cell l a y e r. We suggest that, in this case, a developmental disorder lowered the threshold for the NC-induced seizures and contributed to the establishment of refractory epilepsy.KEY WORDS: refractory epilepsy, neurocysticercosis, dysmorphic neurons. N e u ro c i s t i c e rcose e displasia hipocampal microscópica em paciente com epilepsia do lobo temporal mesial refratária.RESUMO -Estudos epidemiológicos sugerem que a neurocisticercose (NC) é a causa principal de epilepsia sintomática em países em desenvolvimento. A associação entre NC e epilepsia do lobo temporal mesial ( E LTM) tem sido relatada por vários autores. Estudos recentes mostraram que a presença de NC não influên-cia o perfil clínico e patológico em pacientes com ELTM e sugere que nem todas as lesões cisticerc ó t i c a s são inevitavelmente epileptogênicas. No presente estudo, descrevemos uma mulher de 50 anos com crises epilépticas parciais associadas à NC que evolui para ELTM. A paciente foi submetida à cort i c o a m i g d a l ohipocampectomia para tratamento de epilepsia refratária. O estudo imunohistoquímico, utilizando marc a d o res neuronais, foi realizado em seções da formação de hipocampal. Além dos aspectos típicos da esclerose hipocampal, o exame microscópico demonstrou características celulares de malformação hipocampal, incluindo neurônios dismórficos e bilaminação focal da camada granular do giro denteado. Sugerimos que, neste caso, um transtorno do desenvolvimento reduziu o limiar para as crises epilépticas induzidas pela NC e contribuiu para o estabelecimento da epilepsia refratária.PALAVRAS-CHAVE: epilepsia refratária, neurocisticercose, neurônios dismórficos.It has been estimated that 50 million people are i...

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Section: Discussionsupporting

confidence: 91%

Neurocysticercosis and microscopic hippocampal dysplasia in a patient with refractory mesial temporal lobe epilepsy

Silva

Martins

Marques

et al. 2006

Arq. Neuro-Psiquiatr.

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“…These studies have identified important mechanisms leading to specific neuroanatomical pathologies that interrupt normal stages of cortical development. However, seizures can also arise in human brain regions not classified as disorganized Major et al, 2009), and clear evidence for a population of "epileptic" dysplastic neurons has failed to emerge (Cepeda et al, 2003;George and Jacobs, 2011). Using an animal model of human lissencephaly, we show that functional integration of granule cells within the malformed DG is disrupted by LIS1 haploinsufficiency.…”

Section: Discussionmentioning

confidence: 90%

“…Interestingly, acquired epilepsy models are often associated with enhanced proliferation of newborn granule cells (Parent et al, 1997;, but adult-born granule cell survival is reduced in LIS1 mutants . Because dysplastic neurons can also exhibit delayed synaptic maturation (Ackman et al, 2009) and sometimes fail to integrate into functional networks (Cepeda et al, 2003), the synaptic integration of adult-born granule cells might be different in epilepsies associated with an MCD. To address these issues, we used LIS1 mutant, enhanced green fluorescent protein (EGFP) reporter, and conditional knock-out mice in a series of immunohistochemical and electrophysiological studies.…”

Section: Introductionmentioning

confidence: 99%

LIS1 Deficiency Promotes Dysfunctional Synaptic Integration of Granule Cells Generated in the Developing and Adult Dentate Gyrus

et al. 2012

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Type I lissencephaly, a neuronal migration disorder characterized by cognitive disability and refractory epilepsy, is often caused by heterozygous mutations in the LIS1 gene. Histopathologies of malformation-associated epilepsies have been well described, but it remains unclear whether hyperexcitability is attributable to disruptions in neuronal organization or abnormal circuit function. Here, we examined the effect of LIS1 deficiency on excitatory synaptic function in the dentate gyrus of hippocampus, a region believed to serve critical roles in seizure generation and learning and memory. Mice with heterozygous deletion of LIS1 exhibited robust granule cell layer dispersion, and adult-born granule cells labeled with enhanced green fluorescent protein were abnormally positioned in the molecular layer, hilus, and granule cell layer. In whole-cell patch-clamp recordings, reduced LIS1 function was associated with greater excitatory synaptic input to mature granule cells that was consistent with enhanced release probability at glutamatergic synapses. Adult-born granule cells that were ectopically positioned in the molecular layer displayed a more rapid functional maturation and integration into the synaptic network compared with newborn granule cells located in the hilus or granule cell layer or in wild-type controls. In a conditional knock-out mouse, induced LIS1 deficiency in adulthood also enhanced the excitatory input to granule cells in the absence of neuronal disorganization. These findings indicate that disruption of LIS1 has direct effects on excitatory synaptic transmission independent of laminar disorganization, and the ectopic position of adult-born granule cells within a malformed dentate gyrus critically influences their functional maturation and integration.

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“…Mathern and co-workers (103,105,106; for review, see Ref. 104) have extensively investigated the properties of neurons in slices obtained after surgical interventions in migration disorders.…”

Section: Excitatory Gaba In Migration Disordersmentioning

confidence: 99%

GABA: A Pioneer Transmitter That Excites Immature Neurons and Generates Primitive Oscillations

Ben-Ari

Gaı̈arsa

Tyzio

et al. 2007

Physiological Reviews

1,143

1,123

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Developing networks follow common rules to shift from silent cells to coactive networks that operate via thousands of synapses. This review deals with some of these rules and in particular those concerning the crucial role of the neurotransmitter γ-aminobuytric acid (GABA), which operates primarily via chloride-permeable GABAAreceptor channels. In all developing animal species and brain structures investigated, neurons have a higher intracellular chloride concentration at an early stage leading to an efflux of chloride and excitatory actions of GABA in immature neurons. This triggers sodium spikes, activates voltage-gated calcium channels, and acts in synergy with NMDA channels by removing the voltage-dependent magnesium block. GABA signaling is also established before glutamatergic transmission, suggesting that GABA is the principal excitatory transmitter during early development. In fact, even before synapse formation, GABA signaling can modulate the cell cycle and migration. The consequence of these rules is that developing networks generate primitive patterns of network activity, notably the giant depolarizing potentials (GDPs), largely through the excitatory actions of GABA and its synergistic interactions with glutamate signaling. These early types of network activity are likely required for neurons to fire together and thus to “wire together” so that functional units within cortical networks are formed. In addition, depolarizing GABA has a strong impact on synaptic plasticity and pathological insults, notably seizures of the immature brain. In conclusion, it is suggested that an evolutionary preserved role for excitatory GABA in immature cells provides an important mechanism in the formation of synapses and activity in neuronal networks.

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

Cited by 181 publications

References 53 publications

Neurocysticercosis and microscopic hippocampal dysplasia in a patient with refractory mesial temporal lobe epilepsy

Neurocysticercosis and microscopic hippocampal dysplasia in a patient with refractory mesial temporal lobe epilepsy

LIS1 Deficiency Promotes Dysfunctional Synaptic Integration of Granule Cells Generated in the Developing and Adult Dentate Gyrus

GABA: A Pioneer Transmitter That Excites Immature Neurons and Generates Primitive Oscillations

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