Temporal and regional regulation of α1, β2 and β3, but not α2, α4, α5, α6, β1 or γ2 GABAA receptor subunit messenger RNAs following one-week oral flurazepam administration

Tietz, Elizabeth I.; Huang, Xiaoxing; Chen, S.; Ferencak, W.F.

doi:10.1016/s0306-4522(98)00516-8

Cited by 40 publications

(52 citation statements)

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“…Taken together with the findings of in situ hybridization studies, 65,66 the results of these quantitative immunohistochemical studies suggested that changes in the expression of specific GABA A receptor mRNAs (a1 and b3 subunits) were mirrored by changes in their respective subunit proteins. The reliability and validity of using image analysis to make quantitative measurements of changes in chromogen staining density in brain sections were established previously.…”

Section: Discussionmentioning

confidence: 59%

“…13 Although the synaptic mechanisms mediating benzodiazepine tolerance have not been determined, evidence has accumulated that a change in subunit-specific expression of neuronal GABA A receptor subtypes may modify inhibitory function during long-term benzodiazepine treatment. 21,22,27,29,30,44,49,65,66,80,81 Consistent with this hypothesis, time-dependent changes in the mRNA expression of specific GABA A receptor subunits (a1, b2 and b3) were localized to distinct hippocampal and cerebral cortical cell groups, 65,66 following one-week oral flurazepam administration. None the less, no direct link has been provided between changes in GABA A receptor subunit mRNA expression, changes in subunit protein expression and changes in GABA A receptor function.…”

mentioning

confidence: 55%

“…The discrete suppression of GABA A receptor function in CA1 pyramidal cells during prolonged flurazepam administration 47,73,[75][76][77][78] and the associated regionally localized, timedependent reductions in the expression of specific GABA A receptor subunit mRNAs 65,66 warranted quantitative immunohistochemical studies of selected hippocampal and cortical GABA A receptor subunit proteins (a1, a2, b1-3 and g2). Taken together with the findings of in situ hybridization studies, 65,66 the results of these quantitative immunohistochemical studies suggested that changes in the expression of specific GABA A receptor mRNAs (a1 and b3 subunits) were mirrored by changes in their respective subunit proteins.…”

Section: Discussionmentioning

confidence: 99%

“…66,75 Rats were killed for brain section preparation immediately after ending one-week flurazepam administration, when maximal reductions in both a1 and b3 subunit mRNA expression were detected in the hippocampus and cortex. 24,65 Brain section preparation Sections (10 mm) cut from saline-perfused brains derived from flurazepam-treated and matched control rats were postfixed for detection of antibody staining. Immediately after the end of one-week flurazepam or saccharin treatment, rats were anesthetized with ketamine (80 mg/kg, i.m.)…”

Section: Animal Modelmentioning

confidence: 99%

“…The specific goal was to establish whether there is a relationship between the reduced expression of specific GABA A receptor subunit mRNAs in hippocampal and cortical neurons, 65,66 and the expression of selected GABA A receptor subunit proteins (a1, a2, b1-3 and g2). This relationship was investigated after an in vivo benzodiazepine treatment which reliably results in decreased GABA A receptor function in CA1 pyramidal cells, [73][74][75][76][77][78] but not dentate granule cells.…”

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Benzodiazepine-mediated regulation of α1, α2, β1–3 and γ2 GABAA receptor subunit proteins in the rat brain hippocampus and cortex

et al. 1999

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Abstract-Prolonged flurazepam exposure regulates the expression of selected (a1, b2, b3) GABA A receptor subunit messenger RNAs in specific regions of the hippocampus and cortex with a time-course consistent with benzodiazepine tolerance both in vivo and in vitro. In this report, the immunostaining density of six specific GABA A receptor subunit (a1, a2, b1-3 and g2) antibodies was measured in the hippocampus and cortex, among other brain areas, in slide-mounted brain sections from flurazepam-treated and control rats using quantitative computer-assisted image analysis techniques. In parallel with the localized reduction in a1 and b3 subunit messenger RNA expression detected in a previous study, relative a1 and b3 subunit antibody immunostaining density was significantly decreased in flurazepam-treated rat hippocampal CA1, CA3 and dentate dendritic regions, and in specific cortical layers. Quantitative western blot analysis showed that b3 subunit protein levels in crude homogenates of the hippocampal dentate region from flurazepam-treated rats, an area which showed fairly uniform decreases in b3 subunit immunostaining (16-21%), were reduced to a similar degree (18%). The latter findings provide independent support that relative immunostaining density may provide an accurate estimate of protein levels. Consistent with the absence of the regulation of their respective messenger RNAs immediately after ending flurazepam administration, no changes in the density of a2, b1 or b2 subunit antibody immunostaining were found in any brain region. g2 subunit antibody staining was changed only in the dentate molecular layer.The selective changes in GABA A receptor subunit antibody immunostaining density in the hippocampus suggested that a change in the composition of GABA A receptors involving specific subunits (a1 and b3) may be one mechanism underlying benzodiazepine anticonvulsant tolerance. ᭧ 1999 IBRO. Published by Elsevier Science Ltd.Key words: tolerance, flurazepam, quantitative immunohistochemistry, dentate gyrus, limbic system, CA1 pyramidal cells.Although effective anxiolytics and hypnotics, the clinical use of benzodiazepines as anticonvulsants is limited by tolerance development during prolonged administration. A large body of evidence has indicated that benzodiazepine tolerance is related to a reduction in GABA A receptor-mediated fast inhibitory synaptic transmission (for reviews see Refs 2 and 27). The native GABA A receptor is a pentamer composed of combinations of homologous proteins derived from five subunit families with multiple variants (a1-6, b1-4, g1-3, d1 and e1). 8,11,34 The GABA A receptor macromolecule contains binding domains for GABA and several allosteric modulators, including a well-characterized benzodiazepine binding site. 59Benzodiazepines potentiate GABA A receptor-mediated inhibitory function by increasing the opening probability of the integral Cl Ϫ channel, 52,62 and may increase Cl Ϫ channel conductance. 13Although the synaptic mechanisms mediating benzodiazepine tolerance have not been...

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Section: Discussionmentioning

confidence: 59%

mentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Animal Modelmentioning

confidence: 99%

mentioning

confidence: 99%

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Benzodiazepine-mediated regulation of α1, α2, β1–3 and γ2 GABAA receptor subunit proteins in the rat brain hippocampus and cortex

et al. 1999

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Short‐Acting and Other Benzodiazepines

Greenfield¹,

Rosenberg²

2004

The Treatment of Epilepsy

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Downregulation of the α5 subunit of the GABA_A receptor in the pilocarpine model of temporal lobe epilepsy

2003

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ABSTRACT:Specific subunits of ␥-aminobutyric acid (GABA) A receptors may be regulated differentially in animal models of temporal lobe epilepsy during the chronic stage. Although several subunits may be upregulated, other subunits may be downregulated in the hippocampal formation. The ␣5 subunit is of particular interest because of its relatively selective localization in the hippocampus and its potential role in tonic inhibition. In normal rats, immunolabeling of the ␣5 subunit was high in the dendritic layers of CA1 and CA2 and moderate in these regions of CA3. In chronic pilocarpine-treated rats displaying recurrent seizures, ␣5 subunit-labeling was substantially decreased in CA1 and nearly absent in CA2. Only slight decreases in immunolabeling were evident in CA3. In situ hybridization studies demonstrated that the ␣5 subunit mRNA was also strongly decreased in stratum pyramidale of CA1 and CA2. Thus, the alterations in localization of the ␣5 subunit peptide and its mRNA were highly correlated. The large decreases in labeling of the ␣5 subunit did not appear to be related to loss of pyramidal neurons in CA1 or CA2 since these neurons were generally preserved in pilocarpine-treated animals. No comparable decreases in labeling of the ␣2 subunit of the GABA A receptor were detected. These findings indicate that the ␣5 subunit of the GABA A receptor is capable of substantial and prolonged downregulation in remaining pyramidal neurons in a model of temporal lobe epilepsy. The results raise the possibility that presumptive extrasynaptic GABA A receptor subunits, such as the ␣5 subunit, may be regulated differently than synaptically located subunits, such as the ␣2 subunit, within the same brain regions in some pathological conditions. Hippocampus 2003;13:633-645.

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Temporal and regional regulation of α1, β2 and β3, but not α2, α4, α5, α6, β1 or γ2 GABAA receptor subunit messenger RNAs following one-week oral flurazepam administration

Cited by 40 publications

References 63 publications

Benzodiazepine-mediated regulation of α1, α2, β1–3 and γ2 GABAA receptor subunit proteins in the rat brain hippocampus and cortex

Benzodiazepine-mediated regulation of α1, α2, β1–3 and γ2 GABAA receptor subunit proteins in the rat brain hippocampus and cortex

Short‐Acting and Other Benzodiazepines

Downregulation of the α5 subunit of the GABA_A receptor in the pilocarpine model of temporal lobe epilepsy

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Temporal and regional regulation of α1, β2 and β3, but not α2, α4, α5, α6, β1 or γ2 GABAA receptor subunit messenger RNAs following one-week oral flurazepam administration

Cited by 40 publications

References 63 publications

Benzodiazepine-mediated regulation of α1, α2, β1–3 and γ2 GABAA receptor subunit proteins in the rat brain hippocampus and cortex

Benzodiazepine-mediated regulation of α1, α2, β1–3 and γ2 GABAA receptor subunit proteins in the rat brain hippocampus and cortex

Short‐Acting and Other Benzodiazepines

Downregulation of the α5 subunit of the GABAA receptor in the pilocarpine model of temporal lobe epilepsy

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Downregulation of the α5 subunit of the GABA_A receptor in the pilocarpine model of temporal lobe epilepsy