Altered expression of GABAa and GABAb receptor subunit mRNAs in the hippocampus after kindling and electrically induced status epilepticus

Nishimura, Takuya; Schwarzer, Christoph; Gasser, Elisabeth; Kato, Nobuo; Vezzani, Annamaria; Sperk, Günther

doi:10.1016/j.neuroscience.2005.04.013

Cited by 86 publications

(76 citation statements)

References 86 publications

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“…Tonic GABA A R-mediated inhibition is maintained, but its neurosteroid modulation is reduced in granule cells of pilocarpine-treated mice The marked decrease in ␦ subunit labeling at perisynaptic locations on granule cell dendrites is consistent with previous light microscopic findings of decreased ␦ subunit labeling throughout the molecular layer of the dentate gyrus Peng et al, 2004) and decreased ␦ subunit mRNA in several TLE models Elliott et al, 2003;Nishimura et al, 2005). Contrary to our expectations based on the major role of ␦ subunit-containing GABA A Rs in mediating tonic inhibition in the dentate gyrus (Nusser and Mody, 2002;Stell et al, 2003), tonic GABAergic inhibition was maintained in granule cells of pilocarpine-treated mice, but its regulation was altered.…”

Section: Discussionsupporting

confidence: 89%

“…A consistent pattern of GABA A R subunit changes that has been identified in several TLE models includes decreased expression of the ␦ subunit along with increased expression of ␥2 and ␣4 subunits in the dentate gyrus Peng et al, 2004;Nishimura et al, 2005). Interestingly, changes in these subunits could alter both tonic and phasic inhibition in the dentate gyrus.…”

Section: Introductionmentioning

confidence: 57%

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Altered Localization of GABA_AReceptor Subunits on Dentate Granule Cell Dendrites Influences Tonic and Phasic Inhibition in a Mouse Model of Epilepsy

Zhang¹,

Wei²,

Módy³

et al. 2007

J. Neurosci.

211

239

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Complex changes in GABA A receptors (GABA A Rs) in animal models of temporal lobe epilepsy during the chronic period include a decrease in the ␦ subunit and increases in the ␣4 and ␥2 subunits in the dentate gyrus. We used postembedding immunogold labeling to determine whether the subcellular locations of these subunits were also altered in pilocarpine-treated epileptic mice, and related functional changes were identified electrophysiologically. The ultrastructural studies confirmed a decrease in ␦ subunit labeling at perisynaptic locations in the molecular layer of the dentate gyrus where these subunits are critical for tonic inhibition. Unexpectedly, tonic inhibition in dentate granule cells was maintained in the epileptic mice, suggesting compensation by other GABA A Rs. An insensitivity of the tonic current to the neurosteroid tetrahydrodeoxy-corticosterone was consistent with decreased expression of the ␦ subunit. In the pilocarpine-treated mice, ␣4 subunit labeling remained at perisynaptic locations, but increased ␥2 subunit labeling was also found at many perisynaptic locations on granule cell dendrites, consistent with a shift of the ␥2 subunit from synaptic to perisynaptic locations and potential partnership of the ␣4 and ␥2 subunits in the epileptic animals. The decreased ␥2 labeling near the center of synaptic contacts was paralleled by a corresponding decrease in the dendritic phasic inhibition of granule cells in the pilocarpine-treated mice. These GABA A R subunit changes appear to impair both tonic and phasic inhibition, particularly at granule cell dendrites, and could reduce the adaptive responses of the GABA system in temporal lobe epilepsy.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 57%

Altered Localization of GABA_AReceptor Subunits on Dentate Granule Cell Dendrites Influences Tonic and Phasic Inhibition in a Mouse Model of Epilepsy

Zhang¹,

Wei²,

Módy³

et al. 2007

J. Neurosci.

211

239

View full text Add to dashboard Cite

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“…In control animals, GABA A receptors consisting of ␣4 and ␦ subunits are present in the extrasynaptic space and mediate a nonsynaptic form of inhibition, called tonic inhibition (Sur et al, 1999;Nusser and Mody, 2002;Stell and Mody, 2002;Wei et al, 2003;Sun et al, 2004;Mtchedlishvili and Kapur, 2006). Increased expression of ␣4 subunit mRNA and protein in DGCs was demonstrated in animal models of TLE in the past (Brooks-Kayal et al, 1998;Peng et al, 2004;Nishimura et al, 2005). These studies did not clarify whether the ␣4 subunit remains extrasynaptic in epileptic animals or it relocates to synapses.…”

Section: Discussionmentioning

confidence: 99%

Diminished Neurosteroid Sensitivity of Synaptic Inhibition and Altered Location of the α4 Subunit of GABA_AReceptors in an Animal Model of Epilepsy

Sun

Mtchedlishvili

Erişir³

et al. 2007

J. Neurosci.

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In animal models of temporal lobe epilepsy (TLE), neurosteroid sensitivity of GABA A receptors on dentate granule cells (DGCs) is diminished; the molecular mechanism underlying this phenomenon remains unclear. The current study investigated a mechanism for loss of neurosteroid sensitivity of synaptic GABA A receptors in TLE. Synaptic currents recorded from DGCs of epileptic animals (epileptic DGCs) were less frequent, larger in amplitude, and less sensitive to allopregnanolone modulation than those recorded from DGCs of control animals (control DGCs). Synaptic currents recorded from epileptic DGCs were less sensitive to diazepam and had altered sensitivity to benzodiazepine inverse agonist RO 15-4513 (ethyl-8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5␣][1,4]benzodiazepine-3-carboxylate) and furosemide than those recorded from control DGCs. Properties of synaptic currents recorded from epileptic DGCs appeared similar to those of recombinant receptors containing the ␣4 subunit. Expression of the ␣4 subunit and its colocalization with the synaptic marker GAD65 was increased in epileptic DGCs. Location of the ␣4 subunit in relation to symmetric (inhibitory) synapses on soma and dendrites of control and epileptic DGCs was examined with postembedding immunogold electron microscopy. The ␣4 immunogold labeling was present more commonly within the synapse in epileptic DGCs compared with control DGCs, in which the subunit was extrasynaptic. These studies demonstrate that, in epileptic DGCs, the neurosteroid modulation of synaptic currents is diminished and ␣4 subunit-containing receptors are present at synapses and participate in synaptic transmission. These changes may facilitate seizures in epileptic animals.

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“…Allerdings äußern sich die klini schen Sym ptome nach Art der Epilepsie unterschiedlich. Möglicherweise könn ten sie wegen des disinhibitiven Effekts von Etomidat auf die kortikale Aktivität, die durch GABAerge Interneurone ver mittelt wird [10], als Zeichen einer gestei gerten kortikalen Erregbarkeit epilepto gener Netzwerke bei Epilepsiepatienten verstanden werden.…”

Section: Klinische Symptomeunclassified

Aktivierung epileptischer Aktivität durch Etomidat?

et al. 2011

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OriginalarbeitUm den genauen Ursprung epileptischer Aktivität zu beurteilen, kann ein invasives EEG notwendig werden. Damit für die Elektrodenplatzierung der Informationsgewinn aus der nichtinvasiven elektrophysiologischen Diagnostik gesteigert oder die invasive Diagnostik sogar vermieden werden kann, werden pharmakologische Verfahren zur Aktivierung epileptischer Entladungen genutzt. In der vorgestellten Studie wurde zum ersten Mal eine Etomidatnarkose während eines nichtinvasiven Video-EEG-Monitorings (vEEG) von Epilepsiepatienten mit einer Kontrollgruppe verglichen.

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Altered expression of GABAa and GABAb receptor subunit mRNAs in the hippocampus after kindling and electrically induced status epilepticus

Cited by 86 publications

References 86 publications

Altered Localization of GABA_AReceptor Subunits on Dentate Granule Cell Dendrites Influences Tonic and Phasic Inhibition in a Mouse Model of Epilepsy

Altered Localization of GABA_AReceptor Subunits on Dentate Granule Cell Dendrites Influences Tonic and Phasic Inhibition in a Mouse Model of Epilepsy

Diminished Neurosteroid Sensitivity of Synaptic Inhibition and Altered Location of the α4 Subunit of GABA_AReceptors in an Animal Model of Epilepsy

Aktivierung epileptischer Aktivität durch Etomidat?

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Altered expression of GABAa and GABAb receptor subunit mRNAs in the hippocampus after kindling and electrically induced status epilepticus

Cited by 86 publications

References 86 publications

Altered Localization of GABAAReceptor Subunits on Dentate Granule Cell Dendrites Influences Tonic and Phasic Inhibition in a Mouse Model of Epilepsy

Altered Localization of GABAAReceptor Subunits on Dentate Granule Cell Dendrites Influences Tonic and Phasic Inhibition in a Mouse Model of Epilepsy

Diminished Neurosteroid Sensitivity of Synaptic Inhibition and Altered Location of the α4 Subunit of GABAAReceptors in an Animal Model of Epilepsy

Aktivierung epileptischer Aktivität durch Etomidat?

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Altered Localization of GABA_AReceptor Subunits on Dentate Granule Cell Dendrites Influences Tonic and Phasic Inhibition in a Mouse Model of Epilepsy

Altered Localization of GABA_AReceptor Subunits on Dentate Granule Cell Dendrites Influences Tonic and Phasic Inhibition in a Mouse Model of Epilepsy

Diminished Neurosteroid Sensitivity of Synaptic Inhibition and Altered Location of the α4 Subunit of GABA_AReceptors in an Animal Model of Epilepsy