A Genetic Animal Model of Human Neocortical Heterotopia Associated with Seizures

Lee, Kevin M.; Schottler, Frank; Collins, James; Lanzino, Giuseppe; Couture, Daniel E.; Rao, Anand N.; Hiramatsu, Ken Ichiro; Goto, Yasunobu; Hong, Seung Chyul; Caner, Hakan; Yamamoto, Haruaki; Chen, Zong Fu; Bertram, Edward H.; Berr, Stuart S.; Omary, Reed A.; Scrable, Heidi; Jackson, Theodore; Goble, John C.; Eisenman, Leonard M.

doi:10.1523/jneurosci.17-16-06236.1997

Cited by 124 publications

(109 citation statements)

References 31 publications

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“…As in irradiated rats, studies in MAM-treated rats have documented long-range connections between heterotopic gray matter and normal cortical and subcortical targets Yurkewicz et al 1984). Tish rat is a spontaneous mutant that has unprovoked epileptic seizures and a large, tubular mass of heterotopic cortex that lies in the white matter beneath the frontoparietal cortex of each cerebral hemisphere (Lee et al 1997). Heterotopic neurons in this model also show reciprocal connections with cortical and subcortical brain structures (Schottler et al 1998).…”

Section: Discussionmentioning

confidence: 97%

Reduction of Spontaneous Inhibitory Synaptic Activity in Experimental Heterotopic Gray Matter

Chen

Roper

2003

Journal of Neurophysiology

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Chen, Huan-Xin and Steven N. Roper. Reduction of spontaneous inhibitory synaptic activity in experimental heterotopic gray matter. J Neurophysiol 89: 150 -158, 2003. 10.1152/jn.00325.2002. Neuronal heterotopia has a strong association with epilepsy, but the mechanisms that underlie this relationship are largely unknown. We have utilized the in utero irradiated rat model to study circuit abnormalities in experimentally induced subcortical heterotopic gray matter. Spontaneous and miniature inhibitory (IPSCs) and excitatory (EPSCs) postsynaptic currents were recorded from visualized heterotopic pyramidal neurons in in vitro hemispheric slices and compared with control neocortical pyramidal neurons using the whole cell patchclamp technique. The frequency of spontaneous and miniature IPSCs was significantly reduced in pyramidal neurons from heterotopic cortex. Amplitude and kinetics of IPSCs were not different between the two groups. Spontaneous and miniature EPSCs were not different between the two groups. Short-term synaptic plasticity of stimulusevoked EPSCs showed depression in heterotopic neurons and facilitation in control pyramidal neurons. This study shows a selective impairment of the GABAergic circuitry in experimental heterotopic gray matter. We have reported similar findings in normotopic dysplastic cortex from this model. Taken together, these studies demonstrate a pervasive defect in inhibition throughout the cortex of irradiated rats with cortical dysplasia and neuronal heterotopia. This may have important implications regarding cortical development and function following in utero injuries.

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Section: Discussionmentioning

confidence: 97%

Reduction of Spontaneous Inhibitory Synaptic Activity in Experimental Heterotopic Gray Matter

Chen

Roper

2003

Journal of Neurophysiology

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“…2B) extending dorsally from the frontal to the dorsoparietal (apparently unaffected) neocortex (26). The heterotopia is present bilaterally, contains neurons with neocortical appearance, and displays near-normal connections with subcortical targets (27).…”

Section: The Tish Mutantmentioning

confidence: 99%

Cortical Malformations and Epilepsy: New Insights from Animal Models

et al. 1999

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Summary:In the last decade, the recognition of the high frequency of cortical malformations among patients with epilepsy especially children, has led to a renewed interest in the study of the pathophysiology of cortical development. This field has also been spurred by the recent development of several experimental genetic and non-genetic, primarily rodent, models of cortical malformations. Epileptiform activity in these animals can appear as spontaneous seizure activity in vivo, in vitro hyperexcitability, or reduced seizure susceptibility in vitro and in vivo. In the neonatal freeze lesion model, that mimics human microgyria, hyperexcitability is caused by a reorganization of the network in the borders of the malformation. In the prenatal methylazoxymethanol model, that causes a diffuse cortical malformation, hyperexcitability is associated with alteration of firing properties of discrete neuronal subpopulations together with the formation of bridges between normally unconnected structures. In agreement with clinical evidence, these expenmental data suggest that cortical malformations can both form epileptogenic foci and alter brain development in a manner that causes a diffuse hyperexcitability of the cortical network. Key Words: Neocortex-Hippocampus-Development-Neuronal migration-Methylazoxymethanol.As early as the end of the nineteenth century, neuropathologists began to report an association between cortical malformations and epilepsy (1-3). Until recently, however, clinical and experimental research yielded few insights into the pathophysiology of this distinct class of epilepsies. In fact, the last decade has seen three major scientific advances that have directly contributed to the "rediscovery" and renewed interest in examining the cause of epilepsy in patients with cortical malformations: mation and epilepsy. Moreover, neuropathologic analysis of resected tissue has frequently demonstrated the presence of more subtle malformations that were not identified in vivo. 3. Recent progress in human molecular genetics has allowed the identification of several genes whose mutations lead to both malformations and epilepsy. In parallel, several genetic and nongenetic rodent models of cortical malformations were shown to be associated with either spontaneous seizures or hyperexcitability .Our goal is to review the contributions of these animal models to our understanding of the pathophysiology of cortical malformations and to discuss their possible link with epilepsy. CORTICAL MALFORMATIONS IN HUMANSHuman cortical malformations have been the subject of several reviews (4-8) and the histology of the major types of cortical malformations encountered is fairly well established (see Fig. 1). In addition, classification of cortical malformations (based on neuropathology, radiology, etiology, or a combination of these elements) has 811

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“…A particularly useful animal for this purpose is the seizure-prone genetic mutant termed the telencephalic internal structural heterotopia (tish) rat. An autosomal recessive mutation in the tish rat results in the development of bilateral subcortical band heterotopia reminiscent of those found in the human seizure disorder of subcortical band heterotopia or double cortex (Lee et al, 1997). The heterotopia consist of misplaced cortical neurons and glia that retain several basic features of normal neocortex, including topographic connectivity with subcortical targets (Lee et al, 1997Schottler et al, 1998Schottler et al, , 2001).…”

Section: Introductionmentioning

confidence: 99%

“…However, the heterotopic neurons fail to orient and laminate as in typical neocortex. Overlying the heterotopia is an area of the neocortex termed "normotopic cortex" that is thinner than normal neocortex but maintains proper orientation and lamination of its primary neurons (Lee et al, 1997(Lee et al, , 1999Schottler et al, 1998Schottler et al, , 2001. Electrophysiological studies have demonstrated that spontaneous seizure activity occurs in both normotopic and heterotopic areas of the adult tish neocortex, but that the normotopic area is more prone to develop aberrant discharge activity (Chen et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…Electrophysiological studies have demonstrated that spontaneous seizure activity occurs in both normotopic and heterotopic areas of the adult tish neocortex, but that the normotopic area is more prone to develop aberrant discharge activity (Chen et al, 2000). Key advantages of the tish rat for studying functional disturbances associated with a cortical malformation are (1) the heterotopia are genetically heritable (i.e., no experimental manipulation is required to induce the malformation) and (2) the animals are naturally prone to develop recurrent spontaneous seizures (Lee et al, 1997;Chen et al 2000).…”

Section: Introductionmentioning

confidence: 99%

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GABAergic Synaptic Inhibition Is Reduced before Seizure Onset in a Genetic Model of Cortical Malformation

Trotter¹,

Kapur²,

Anzivino³

et al. 2006

J. Neurosci.

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Malformations of the neocortex are a common cause of human epilepsy; however, the critical issue of how disturbances in cortical organization render neurons epileptogenic remains controversial. The present study addressed this issue by studying inhibitory structure and function before seizure onset in the telencephalic internal structural heterotopia (tish) rat, which is a genetic model of heightened seizure susceptibility associated with a prominent neocortical malformation. Both normally positioned (normotopic) and misplaced (heterotopic) pyramidal neurons in the tish neocortex exhibited lower resting membrane potentials and a tendency toward higher input resistance compared with pyramidal neurons from control brains. GABAergic synaptic transmission was attenuated in the tish cortex, characterized by significant reductions in the frequency of spontaneous IPSCs (sIPSCs) and miniature IPSCs recorded from pyramidal neurons. In addition, the amplitudes of sIPSCs were reduced in the tish neocortex, an effect that was more profound in the normotopic cells. Immunohistochemical assessment of presynaptic GABAergic terminals showed a reduction in terminals surrounding pyramidal cell somata in normotopic and heterotopic tish neocortex. The attenuation of inhibitory innervation was more prominent for normotopic neurons and was associated with a reduction in a subset of GABAergic interneurons expressing the calcium-binding protein parvalbumin. Together, these findings indicate that key facets of inhibitory GABAergic neurotransmission are disturbed before seizure onset in a brain predisposed to developing seizures. Such alterations represent a rational substrate for reduced seizure thresholds associated with certain cortical malformations.

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A Genetic Animal Model of Human Neocortical Heterotopia Associated with Seizures

Cited by 124 publications

References 31 publications

Reduction of Spontaneous Inhibitory Synaptic Activity in Experimental Heterotopic Gray Matter

Reduction of Spontaneous Inhibitory Synaptic Activity in Experimental Heterotopic Gray Matter

Cortical Malformations and Epilepsy: New Insights from Animal Models

GABAergic Synaptic Inhibition Is Reduced before Seizure Onset in a Genetic Model of Cortical Malformation

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