Differential expression of glutamate and GABA-A receptor subunit mRNA in cortical dysplasia

Crino, Peter B.; Duhaime, Anne–Christine; Baltuch, Gordon H.; White, Ricarda

doi:10.1212/wnl.56.7.906

Cited by 166 publications

(125 citation statements)

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“…Studies performed in humans and other animal models have implicated disruptions in the GABAergic system in seizure activity. These disruptions include altered inhibitory drive (Smith et al, 1999;Zhu and Roper, 2000;Calcagnotto et al, 2002), alterations in GABA interneuron populations (Ferrer et al, 1994;Mathern et al, 1995;Jacobs et al, 1996;Marco et al, 1996;Hablitz and DeFazio, 1998;Rosen et al, 1998;Spreafico et al, 1998;Roper et al, 1999;Schwarz et al, 2000), changes in GABA A receptor subunits (DeFazio and Hablitz, 1999;Loup et al, 2000;Redecker et al, 2000;Coulter, 2001;Crino et al, 2001;White et al, 2001;Palma et al, 2005), and changes in GABA reuptake transporters (Calcagnotto et al, 2002(Calcagnotto et al, , 2005). An important remaining question is what events precipitate the onset of seizures against this background of reduced inhibition.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…This approach has been implemented in human and experimental epilepsy models and in live, as well as fixed, cell types (10)(11)(12)(13). The use of an oligo-dT primer and T7 RNA polymerase permits amplification of a broad population of expressed genes across many gene families.…”

Section: Discussionmentioning

confidence: 99%

Differential Expression of GABA and Glutamate‐receptor Subunits and Enzymes Involved in GABA Metabolism between Electrophysiologically Identified Hippocampal CA1 Pyramidal Cells and Interneurons

Telfeian¹,

Tseng

Baybis

et al. 2003

Epilepsia

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Summary: Purpose:The balance between synaptic excitation and inhibition within the hippocampus is critical for maintaining normal hippocampal function. Even mild reduction in inhibition or enhancement of excitation can produce seizures. Synaptic excitation is produced by pyramidal cells and granule cells, whereas inhibition is produced by a smaller number of interneurons. To understand how two subpopulations of these excitatory and inhibitory neurons are regulated at the molecular level, we analyzed specific mRNA expression profiles for receptors that are significantly involved in synaptic transmission and in the synthesis and storage of the principal inhibitory neurotransmitter, ␥-aminobutyric acid (GABA). Our hypothesis was that differences in gene expression between inhibitory and excitatory neurons in the rat hippocampus might point to specific new targets for seizure pharmacotherapy.Methods: We combined the techniques of (a) whole-cell patch clamping in rat hippocampal slices, (b) biocytin staining for cell identification, (c) single-cell mRNA amplification, and (d) small-scale cDNA microarray analysis to allow us to obtain expression profiles for candidate genes from identified CA1 pyramidal neurons and interneurons. Electrophysiologic and morphologic data and expression profiles were obtained from 12 stratum pyramidale and seven stratum radiatum cells.Results: Presumed inhibitory neurons expressed significantly more GAD65, GAD67, vGAT, GABA A -receptor ␣3, and N-methyl-D-aspartate (NMDA)-receptor IIB mRNA, and presumed excitatory neurons expressed more GABA A -receptor ␣1, and NMDA-receptor I mRNA.Conclusions: Differential expression of candidate neurotransmitter-receptor subunits distinguished CA1 pyramidal neurons from interneurons. These differences may indicate potential new targets for altering the balance of inhibition and excitation in the treatment of epilepsy. Key Words: mRNA-GABA-Hippocampus-Interneuron-Brain slice-Epilepsy.Hippocampal excitatory and inhibitory neurons differ from one another in a variety of features including morphology, action potential-firing characteristics, neurotransmitter choice, peptide composition, calcium-binding protein composition, neurotransmitter-receptor subunit expression, and neurotransmitter release mechanisms (1). There are likely to be many other fundamental differences between these two classes of neurons. In general, these differences have been detected when new techniques or reagents have become available and are then applied to neurons of interest, for example, immunohistochemistry with a new antibody, or molecular techniques to identify newly cloned receptors. It would be useful if a simultaneous identification of many of these phenotypic characteristics of inhibitory interneurons could be determined in a cell-type-specific manner. This would allow identification of the expression of genes of interest and unknown genes that subserve important functions in these neurons and could serve to establish a coordinated molecular phenotype of the neurons in quest...

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“…Among the iGluRs, the role of N-methyl-Daspartate (NMDA) receptors (GluN) in cortical hyperexcitability has received considerable attention. Several studies have shown alteration in GluN subunit expression in human epileptic tissue with increased expression of the subunit NR2B [149][150][151][152]. Changes in the expression of components of the membrane-associated guanylate kinase (MAGUK) protein family, interacting with GluN, has been also reported [153,154].…”

Section: Epileptogenesismentioning

confidence: 99%

“…In particular, recent data showing upregulation of NMDA regulatory subunits and related MAGUK proteins in epileptogenic/dysplastic areas suggest that glutamate/NMDA/ MAGUK dysregulation might also represent the intracellular trigger that modifies brain morphology and induces cell death [154]. Alteration in the expression of α-amino-3-hydroxy-5-methyl-4-isixazolepropionic acid receptor subtypes has been also reported ( [150]; for reviews see [146] and [147]). In addition to the deregulation of iGluR, the cellular distribution of mGluR subtypes, with high expression of mGluR1α and mGluR5 in dysmorphic neurons, suggests a possible contribution of group I mGluRs to the intrinsic and high epileptogenicity of dysplastic cortical regions [155].…”

Section: Epileptogenesismentioning

confidence: 99%

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

Aronica

Crino

2014

Neurotherapeutics

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Differential expression of glutamate and GABA-A receptor subunit mRNA in cortical dysplasia

Cited by 166 publications

References 37 publications

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

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

Differential Expression of GABA and Glutamate‐receptor Subunits and Enzymes Involved in GABA Metabolism between Electrophysiologically Identified Hippocampal CA1 Pyramidal Cells and Interneurons

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

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