Time-dependent and regional expression of GABA transporter mRNAs following amygdala-kindled seizures in rats

Hirao, Toshihide; Morimoto, Kiyoshi; Yamamoto, Yoshitaka; Watanabe, Takemi; Sato, Hitoshi; Satô, Keiko; Sakata, Soichiro; Yamada, Norihito; Tanaka, Kōichi; Sekiya, Hiroshi

doi:10.1016/s0169-328x(97)00323-9

Cited by 37 publications

(19 citation statements)

References 46 publications

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“…In agreement with previous reports (Durkin et al, 1995;Hirao et al, 1998;Frahm et al, 2000), GAT-1 mRNA was found in numerous interneurons and in the granule cell layer of the dorsal and ventral hippocampus (Fig. 3A,C).…”

Section: Plasma Membrane Gaba Transporters (Gat-1 and Gat-3)supporting

confidence: 93%

Expression of plasma membrane GABA transporters but not of the vesicular GABA transporter in dentate granule cells after kainic acid seizures

et al. 2003

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Kainic acid-induced seizures cause a marked increase in the expression of glutamate decarboxylase 67 (GAD67) in granule cells of the dentate gyrus. To determine the possible modes of sequestration of newly formed gamma-aminobutyric acid (GABA), we used in situ hybridization and immunocytochemistry to investigate the expression of several proteins related to GABA in dentate granule cells of rats 4 h to 60 days after kainic acid-induced status epilepticus and in controls. GAD67 and GAD65 mRNA levels were increased by up to 300% and 800%, respectively, in the granule cell layer 6-24 h after kainate injection. Subsequently, increased GAD and GABA immunoreactivity was observed in the terminal field of mossy fibers and in presumed dendrites of granule cells. mRNA of both known plasma membrane GABA transporters (GAT-1 and GAT-3) was expressed in granule cells of control rats. GAT-1 mRNA levels increased (by 30%) 9 h after kainate injection but were reduced by about 25% at later intervals. GAT-3 mRNA was reduced (by 35-75%) in granule cells 4 h to 30 days after kainic acid injection. In contrast, no expression of the mRNA or immunoreactivity of the vesicular GABA transporter was detected in granule cells or in mossy fibers, respectively. GABA transaminase mRNA was only faintly expressed in granule cells, and its levels were reduced (by 60-65%) 12 h to 30 days after kainate treatment. The results indicate that GABA can be taken up and synthesized in granule cells. No evidence for the expression of the vesicular GABA transporter (VGAT) in granule cells was obtained. After sustained epileptic seizures, the markedly increased expression of glutamate decarboxylase and the reduced expression of GABA transaminase may result in increased cytoplasmic GABA concentrations in granule cells. It is suggested that, during epileptic seizures, elevated intracellular GABA and sodium concentration could then result in nonvesicular release of GABA from granule cell dendrites. GABA could then act on GABA-A receptors, protecting granule cells from overexcitation.

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Section: Plasma Membrane Gaba Transporters (Gat-1 and Gat-3)supporting

confidence: 93%

Expression of plasma membrane GABA transporters but not of the vesicular GABA transporter in dentate granule cells after kainic acid seizures

et al. 2003

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“…Indeed, studies to elucidate the physiological significance of GAT activity during excitotoxic and ischemic insults in mammals have provided contradictive results. Whereas some studies have reported decreased GAT1 and GAT3 expression (27,44), others have reported increased expression (18,27). These contradictions may reflect different GATs serving different roles in different biological systems or contexts.…”

Section: Discussionmentioning

confidence: 94%

“…Total RNA (1 g) was DNase I treated and reverse transcribed using oligo(dT) 18 and Superscript III, as previously described. For each fish, duplicate cDNA syntheses were performed.…”

Section: Rna Extraction and Cdna Synthesis For Real-time Rt-pcrmentioning

confidence: 99%

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Expression of genes involved in GABAergic neurotransmission in anoxic crucian carp brain (Carassius carassius)

Ellefsen

Stensløkken

Fagernes

et al. 2009

Physiological Genomics

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Ellefsen S, Stensløkken K, Fagernes CE, Kristensen TA, Nilsson GE. Expression of genes involved in GABAergic neurotransmission in anoxic crucian carp brain (Carassius carassius). Physiol Genomics 36: 61-68, 2009. First published October 28, 2008 doi:10.1152/physiolgenomics.90301.2008.-The crucian carp, Carassius carassius, survives days to months without oxygen, depending on temperature. In the anoxic crucian carp brain, increased GABAergic inhibition, mediated by increased extracellular levels of GABA, has been shown to suppress electric activity and ATP consumption. To investigate an involvement of gene expression in this response, we utilized real-time RT-PCR to test the effect of 1 and 7 days anoxia (8°C) on the expression of 22 genes, including nine GABAA receptor subunits (␣1-6, ␤2, ␦, and ␥2), three GABAB receptor subunits (GB1a-1b and GB2), three enzymes involved in GABA metabolism (GAD65 and GAD67, GABAT), four GABA transporters (GAT1, 2a-b and 3), two GABAA receptor-associated proteins (GABARAP 1 and 2), and the K ϩ /Cl Ϫ cotransporter KCC2. While the expression of GABAA receptor subunits was dominated by ␣4-, ␣6-, and ␦-subunits, all of which are located to extrasynaptic sites in mammalian brains and respond to elevations in extracellular levels of GABA by showing tonic activity patterns, the expression of GABA transporters was dominated by GAT2 (a and b) and GAT3, which also show extrasynaptic location in mammals. These expression patterns differ from those observed in mammals and may be a prerequisite for GABAergic inhibition of anoxic metabolic rate in crucian carp. Furthermore, while the expression of the majority of the genes was largely unaltered by anoxia, the expression of GAT2 and GAT3 decreased to 20%. This suggests impairment of GABA transport, which could be a mechanism behind the accumulation of extracellular GABA and the increased GABAergic inhibition.GABA; GABA receptor; GABA transporter; external RNA control SINCE GABA IS THE DOMINANT inhibitory neurotransmitter in vertebrate brains, GABAergic neurotransmission has been suggested to function as an endogenous defense against excitotoxic events, such as the excessive release of glutamate during periods of ischemia/anoxia (26). However, GABAergic activity seems to be lowered rather than enhanced in ischemic mammalian brains, resulting in neuronal hyperexcitability and cell death (41). Thus, efforts have been made to reverse this process, and several studies have found that artificially increased GABAergic activity results in increased neuroprotection (41).Interestingly, anoxia induces increased GABA levels and GABAergic activity in brains of vertebrate species that tolerate prolonged periods of oxygen depletion, such as fish of the genus Carassius and freshwater turtles of genera Chrysemys and Trachemys. For example, while crucian carp (Carassius carassius) brains show a doubling of extracellular GABA levels after 6 h of anoxia and a fivefold increase in tissue GABA levels after prolonged anoxia (32, 19), freshwater turtle brains show a ...

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“…A signi®cant decrease in the GABA uptake carrier density after amygdala kindling has been reported (During et al, 1995), associated with changes in the mRNA encoding for the GABA uptake carrier type I (Hirao et al, 1998). One reason may be that alterations are regionally speci®c.…”

Section: Discussionmentioning

confidence: 99%

Effect of amygdala kindling on the central nervous system effects of tiagabine: EEG effects versus brain GABA levels

Cleton

Altorf

Voskuyl

et al. 2000

British J Pharmacology

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1 The objective of this investigation was to determine the in¯uence of amygdala kindling on the pharmacodynamics of tiagabine in vivo, using quantitative EEG parameters and extracellular GABA concentrations as pharmacodynamic endpoints. In integrated pharmacokinetic/pharmacodynamic (PK/PD) studies the time course of these eects was determined in conjunction with plasma concentrations following intravenous administration of 10 mg kg71 . An`eect compartment' model was used to derive individual concentration ± eect relationships. 2 Tiagabine produced an increase in the amplitude of the 11.5 ± 30 Hz frequency band of the EEG. The relationship between concentration and EEG eect was non-linear and described by the Hill equation. In kindled rats the EC 50 was reduced to 291 ng ml 71 from the original value of 521 ng ml 71 in controls. The values of all other parameters were unchanged. 3 In kindled rats the baseline extracellular GABA concentration was increased to 1.58 mM from 0.74 mM in controls. The relationships between tiagabine concentration and extracellular GABA concentration were again non-linear and described by the Hill equation. No dierences were observed between kindled rats and controls. In the synaptoneurosmal preparation in vitro no changes in the functioning of the GABA transporter were observed. 4 It is concluded that unlike the situation with midazolam, there is no resistance to the EEG eect of tiagabine in the kindling model of experimental epilepsy. The observed shift in the concentration ± EEG eect relationship to lower concentrations can presumably be explained by the increase in the baseline GABA levels.

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Time-dependent and regional expression of GABA transporter mRNAs following amygdala-kindled seizures in rats

Cited by 37 publications

References 46 publications

Expression of plasma membrane GABA transporters but not of the vesicular GABA transporter in dentate granule cells after kainic acid seizures

Expression of plasma membrane GABA transporters but not of the vesicular GABA transporter in dentate granule cells after kainic acid seizures

Expression of genes involved in GABAergic neurotransmission in anoxic crucian carp brain (Carassius carassius)

Effect of amygdala kindling on the central nervous system effects of tiagabine: EEG effects versus brain GABA levels

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