Selective changes in single cell GABAA receptor subunit expression and function in temporal lobe epilepsy

Brooks‐Kayal, Amy R.; Shumate, Melissa D.; Ji, Hong; Rikhter, Tatiana Y.; Coulter, Douglas A.

doi:10.1038/2661

Cited by 709 publications

(588 citation statements)

References 39 publications

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“…However, GABAergic interneurons undergo marked cell death in the hippocampus of epileptic rats (Schwarzer and Sperk, 1995;Andre et al, 2001). The lack of change in GABA concentration is in accordance with the upregulation of the GABA neuronal marker, glutamate decarboxylase (GAD), observed in the seizure circuit during the latent and long-term phases of Li-pilo and pilocarpine models (Brooks-Kayal et al, 1998;Andre et al, 2001) However, labeling of [2-13 C]GABA from [1-13 C]glucose was decreased, indicating decreased turnover of GABA, in agreement with the previously reported decreased release (Hirsch et al, 1999). Conversely, labeling of GABA from [1,2-13 C]acetate in astrocytes was unchanged.…”

Section: Gabasupporting

confidence: 57%

Metabolism is Normal in Astrocytes in Chronically Epileptic Rats: A ¹³C NMR Study of Neuronal—Glial Interactions in a Model of Temporal Lobe Epilepsy

Melø

Nehlig

Sonnewald

2005

J Cereb Blood Flow Metab

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The aim of the present work was to study potential disturbances in metabolism and interactions between neurons and glia in the lithium-pilocarpine model of temporal lobe epilepsy. Rats chronically epileptic for 1 month received [1-13 C]glucose, a substrate for neurons and astrocytes, and [1,2-13 C]acetate, a substrate for astrocytes only. Analyses of extracts from cerebral cortex, cerebellum, and hippocampal formation (hippocampus, amygdala, entorhinal, and piriform cortices) were performed using 13 C and 1 H nuclear magnetic resonance spectroscopy and HPLC. In the hippocampal formation of epileptic rats, levels of glutamate, aspartate, N-acetyl aspartate, adenosine triphosphate plus adenosine diphosphate and glutathione were decreased. In all regions studied, labeling from [1,2-13 C]acetate was similar in control and epileptic rats, indicating normal astrocytic metabolism. However, labeling of glutamate, GABA, aspartate, and alanine from [1-13 C]glucose was decreased in all areas possibly reflecting neuronal loss. The labeling of glutamine from [1-13 C]glucose was decreased in cerebral cortex and cerebellum and unchanged in hippocampal formation. In conclusion, no changes were detected in glial-neuronal interactions in the hippocampal formation while in cortex and cerebellum the flow of glutamate to astrocytes was decreased, indicating a disturbed glutamate-glutamine cycle. This is, to our knowledge, the first study showing that metabolic disturbances are confined to neurons inside the epileptic circuit.

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Section: Gabasupporting

confidence: 57%

Metabolism is Normal in Astrocytes in Chronically Epileptic Rats: A ¹³C NMR Study of Neuronal—Glial Interactions in a Model of Temporal Lobe Epilepsy

Melø

Nehlig

Sonnewald

2005

J Cereb Blood Flow Metab

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“…According to these experiments, the augmented inhibition found in the epileptic tissue is however decreased by the Zn 2+ that is released from aberrantly sprouted mossy fiber terminals of granule cells during seizures. Evidence has also been obtained for selective changes in receptor subunit expression in animal models of TLE (Kamphuis et al, 1994(Kamphuis et al, , 1995Rice et al, 1996;Brooks-Kayal et al, 1998).…”

Section: Gaba a Receptor-mediated Inhibition In Temporal Lobe Epilepsymentioning

confidence: 99%

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

Avoli¹,

Curtis²

2011

Progress in Neurobiology

228

253

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GABA is the main inhibitory neurotransmitter in the adult forebrain, where it activates ionotropic type A and metabotropic type B receptors. Early studies have shown that GABA A receptormediated inhibition controls neuronal excitability and thus the occurrence of seizures. However, more complex, and at times unexpected, mechanisms of GABAergic signaling have been identified during epileptiform discharges over the last few years. Here, we will review experimental data that point at the paradoxical role played by GABA A receptor-mediated mechanisms in synchronizing neuronal networks, and in particular those of limbic structures such as the hippocampus, the entorhinal and perirhinal cortices, or the amygdala. After having summarized the fundamental characteristics of GABA A receptor-mediated mechanisms, we will analyze their role in the generation of network oscillations and their contribution to epileptiform synchronization. Whether and how GABA A receptors influence the interaction between limbic networks leading to ictogenesis will be also reviewed. Finally, we will consider the role of altered inhibition in the human epileptic brain along with the ability of GABA A receptor-mediated conductances to generate synchronous depolarizing events that may lead to ictogenesis in human epileptic disorders as well.

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“…The antibody against α4 subunit (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) has been characterized previously [1,12,32]. The antibodies against the γ2 (1-33) and δ (1-44) subunit of the GABA A receptor have been characterized extensively in the past by immunoprecipitation, Western blot, and immunohistochemistry [11,[19][20][21][22]32].…”

Section: Antibodiesmentioning

confidence: 99%

“…In addition to cerebellar granule cells, dentate granule cells in the hippocampus also express the δ subunit mRNA and polypeptide [3,32]. The α6 subunit is not expressed in these neurons and the δ subunit is believed to combine with the α4 subunit to form functional receptors [34].…”

Section: Introductionmentioning

confidence: 99%

Distribution of α1, α4, γ2, and δ subunits of GABAA receptors in hippocampal granule cells

2004

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GABA A receptors are pentamers composed of subunits derived from the α, β, γ, δ, θ, ε, and π gene families. α1, α4, γ2, and δ subunits are expressed in the dentate gyrus of the hippocampus, but their subcellular distribution has not been described. Hippocampal sections were double-labeled for the α1, α4, γ2, and δ subunits and GAD65 or gephyrin, and their subcellular distribution on dentate granule cells was studied by means of confocal laser scanning microscopy (CLSM). The synaptic versus extrasynaptic localization of these subunits was inferred by quantitative analysis of the frequency of colocalization of various subunits with synaptic markers in high-resolution images. GAD65 immunoreactive clusters colocalized with 26.24±0.86% of the α1 subunit immunoreactive clusters and 32.35±1.49% of the γ2 subunit clusters. In contrast, only 1.58±0.13% of the α4 subunit immunoreactive clusters and 1.92±0.15% of the δ subunit clusters colocalized with the presynaptic marker GAD65. These findings were confirmed by studying colocalization with immunoreactivity of a postsynaptic marker, gephyrin, which colocalized with 27.61±0.16% of the α1 subunit immunoreactive clusters and 23.45±0.32% of the γ2 subunit immunoreactive clusters. In contrast, only 1.90±0.13% of the α4 subunit immunoreactive clusters and 1.76±0.10% of the δ subunit clusters colocalized with gephyrin. These studies demonstrate that a subset of α1 and γ2 subunit clusters colocalize with synaptic markers in hippocampal dentate granule cells. Furthermore, all four subunits, α1, α4, γ2, and δ, are present in the extrasynaptic locations.

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Selective changes in single cell GABAA receptor subunit expression and function in temporal lobe epilepsy

Cited by 709 publications

References 39 publications

Metabolism is Normal in Astrocytes in Chronically Epileptic Rats: A ¹³C NMR Study of Neuronal—Glial Interactions in a Model of Temporal Lobe Epilepsy

Metabolism is Normal in Astrocytes in Chronically Epileptic Rats: A ¹³C NMR Study of Neuronal—Glial Interactions in a Model of Temporal Lobe Epilepsy

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

Distribution of α1, α4, γ2, and δ subunits of GABAA receptors in hippocampal granule cells

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Selective changes in single cell GABAA receptor subunit expression and function in temporal lobe epilepsy

Cited by 709 publications

References 39 publications

Metabolism is Normal in Astrocytes in Chronically Epileptic Rats: A 13C NMR Study of Neuronal—Glial Interactions in a Model of Temporal Lobe Epilepsy

Metabolism is Normal in Astrocytes in Chronically Epileptic Rats: A 13C NMR Study of Neuronal—Glial Interactions in a Model of Temporal Lobe Epilepsy

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

Distribution of α1, α4, γ2, and δ subunits of GABAA receptors in hippocampal granule cells

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Metabolism is Normal in Astrocytes in Chronically Epileptic Rats: A ¹³C NMR Study of Neuronal—Glial Interactions in a Model of Temporal Lobe Epilepsy

Metabolism is Normal in Astrocytes in Chronically Epileptic Rats: A ¹³C NMR Study of Neuronal—Glial Interactions in a Model of Temporal Lobe Epilepsy