Differential seizure response in two models of cortical heterotopia

Gabel, Lisa A.; Manglani, Monica; Ibanez, Natalia; Roberts, Jessica K.; Ramos, Raddy L.; Rosen, Glenn D.

doi:10.1016/j.brainres.2012.11.040

Cited by 11 publications

(9 citation statements)

References 23 publications

(49 reference statements)

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“…Heterotopia in control and experimentally-treated mice may affect performance on the task(s) tested or interact with treatment regimes. This assertion is supported by previous findings that mice with MLH exhibit deficits in learning, memory [28–30,32], and sensory discrimination tasks [33,34,36] as well as neocortical hyperexcitability based on response to chemi-convulsant treatment [38,49]. Finally, the extent to which gene/protein expression changes are observed in neurons and glia in heterotopia remains unknown; these changes could affect neocortical expression studies, particularly when the presence/absence of heterotopia is not known prior to tissue harvesting.…”

Section: Discussionsupporting

confidence: 81%

“…Moreover, mice with heterotopia exhibit impaired learning of spatial and non-spatial memory tasks [28–32] and deficits in sensory discrimination tasks [33–36], consistent with cognitive deficits associated with MLH. Furthermore, mice with MLH have lower seizure thresholds and shorter latency to seizures following chemi-convulsant treatment [37,38], which mimic brain excitability changes observed in epileptics with MLH. Thus, behavioral changes in mice with MLH closely resemble those observed in humans with MLH, demonstrating the utility of mice as a model of human MLH.…”

Section: Introductionmentioning

confidence: 99%

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Divergence and inheritance of neocortical heterotopia in inbred and genetically-engineered mice

Toia

Cuoco

Esposito

et al. 2017

Neuroscience Letters

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Cortical function emerges from the intrinsic properties of neocortical neurons and their synaptic connections within and across lamina. Neurodevelopmental disorders affecting migration and lamination of the neocortex result in cognitive delay/disability and epilepsy. Molecular layer heterotopia (MLH), a dysplasia characterized by over-migration of neurons into layer I, are associated with cognitive deficits and neuronal hyperexcitability in humans and mice. The breadth of different inbred mouse strains that exhibit MLH and inheritance patterns of heterotopia remain unknown. A neuroanatomical survey of numerous different inbred mouse strains, 2 first filial generation (F1) hybrids, and one consomic strain (C57BL/6J-Chr 1A/J/NaJ) revealed MLH only in C57BL/6 mice and the consomic strain. Heterotopia were observed in numerous genetically-engineered mouse lines on a congenic C57BL/6 background. These data indicate that heterotopia formation is a weakly penetrant trait requiring homozygosity of one or more C57BL/6 alleles outside of chromosome 1. These data are relevant toward understanding neocortical development and disorders affecting neocortical lamination.

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Divergence and inheritance of neocortical heterotopia in inbred and genetically-engineered mice

Toia

Cuoco

Esposito

et al. 2017

Neuroscience Letters

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“…Taken together, these data indicate that there exists a diverse complement of neurons in MLH and suggest that these neurons may participate in a synaptic network that contributes to the cortical dysfunction manifested by patients with MLH. Consistent with this hypothesis, mice with MLH have impaired learning of spatial and nonspatial memory tasks [24,25,26,27,28], sensory processing deficits [29,30,31,32] and increased seizure susceptibility [34]. Future studies should be aimed at characterizing the synaptic circuitry and physiological profile of neurons in C57BL/6J mice with MLH, toward gaining a better understanding of how heterotopia cause cortical dysfunction.…”

Section: Discussionmentioning

confidence: 98%

“…Thus, findings in mice with MLH mimic the cognitive defects seen in humans with MLH. Furthermore, we have shown that mice with MLH also have lower seizure thresholds and shorter latency to seizures following chemi-convulsant treatment [33,34], which mimic the brain excitability changes observed in epileptic humans with MLH. Thus, behavioral changes in mice with MLH closely resemble those observed in humans with MLH, demonstrating the utility of mice as a model of human MLH.…”

Section: Introductionmentioning

confidence: 99%

Cellular and Axonal Constituents of Neocortical Molecular Layer Heterotopia

et al. 2014

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Human neocortical molecular layer heterotopia consist of aggregations of hundreds of neurons and glia in the molecular layer (layer I) and are indicative of neuronal migration defect. Despite having been associated with dyslexia, epilepsy, cobblestone lissencephaly, polymicrogyria, and Fukuyama muscular dystrophy, a complete understanding of the cellular and axonal constituents of molecular layer heterotopia is lacking. Using a mouse model, we identify diverse excitatory and inhibitory neurons as well as glia in heterotopia based on molecular profiles. Using immunocytochemistry, we identify diverse afferents in heterotopia from subcortical neuromodulatory centers. Finally, we document intracortical projections to/from heterotopia. These data are relevant toward understanding how heterotopia affect brain function in diverse neurodevelopmental disorders.

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“…Other models were only reported to exhibit increased susceptibility to convulsant-evoked seizures: pilocarpine-induced seizures in Heco mice [51] and RA-GEF-1 conditional KO [111]. Surprisingly, BXD29-Trl4lps 2J/J mice were found more resistant to PTZ-induced seizures than wild-type controls [112]. Seizure susceptibility was not investigated in RhoA conditional KO.…”

Section: Spontaneous and Induced Seizures In Sbh Modelsmentioning

confidence: 99%

Causes and Consequences of Gray Matter Heterotopia

et al. 2014

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The objective of this article is to review the pathophysiological bases of gray matter heterotopia and to appreciate their involvement in brain cortical development and functional consequences, namely epilepsy. The development of the cerebral cortex results from complex sequential processes including cell proliferation, cell migration, cortical organization, and formation of neuronal networks. Disruption of these steps yields different types of cortical malformations including gray matter heterotopia, characterized by the ectopic position of neurons along the ventricular walls or in the deep white matter. Cortical malformations are major causes of epilepsy, being responsible for up to 40% of drug-resistant epilepsy, and the cognitive level of affected patients varies from normal to severely impaired. This review reports data from human patients and animal models highlighting the genetic causes for these disorders affecting not only neuronal migration but also the proliferation of cortical progenitors. Therefore, gray matter heterotopias should not be considered as solely due to an abnormal neuronal migration and classifying them as such may be too restrictive. The review will also summarize literature data indicating that besides ectopic neurons, neighbor cortical areas also play a consistent role in epileptogenesis, supporting the notion that plastic changes secondary to the initial malformation are instrumental in the pathophysiology of epilepsy in affected patients.

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Differential seizure response in two models of cortical heterotopia

Cited by 11 publications

References 23 publications

Divergence and inheritance of neocortical heterotopia in inbred and genetically-engineered mice

Divergence and inheritance of neocortical heterotopia in inbred and genetically-engineered mice

Cellular and Axonal Constituents of Neocortical Molecular Layer Heterotopia

Causes and Consequences of Gray Matter Heterotopia

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