Changes in hippocampal GABAA/cBZR density during limbic epileptogenesis: Relationship to cell loss and mossy fibre sprouting

Vivash, Lucy; Tostevin, Anna; Liu, Dsh; Dalic, Linda J.; Dedeurwaerdere, Stefanie; Hicks, Rodney J.; Williams, D. A.; Myers, Damian E.; O’Brien, Terence J.

doi:10.1016/j.nbd.2010.08.021

Cited by 23 publications

(25 citation statements)

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“…Synaptically localized GABA A receptors were unchanged, as indicated by the immunoreactivity of postsynaptic GABA A receptors [39]. Vivash et al reported that GABA A receptor density was reduced in epilepsy rats [40]. Here, we suggest that the use of oral UR for 6 weeks can dramatically reduce epileptic symptoms without changing GABA A receptor density.…”

Section: Discussionmentioning

confidence: 65%

Neuroprotective Effect ofUncaria rhynchophyllain Kainic Acid-Induced Epileptic Seizures by Modulating Hippocampal Mossy Fiber Sprouting, Neuron Survival, Astrocyte Proliferation, and S100B Expression

Liu

Lin

Tang

et al. 2012

Evidence-Based Complementary and Alternative Medicine

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Uncaria rhynchophylla (UR), which is a traditional Chinese medicine, has anticonvulsive effect in our previous studies, and the cellular mechanisms behind this are still little known. Because of this, we wanted to determine the importance of the role of UR on kainic acid- (KA-) induced epilepsy. Oral UR for 6 weeks can successfully attenuate the onset of epileptic seizure in animal tests. Hippocampal mossy fiber sprouting dramatically decreased, while neuronal survival increased with UR treatment in hippocampal CA1 and CA3 areas. Furthermore, oral UR for 6 weeks significantly attenuated the overexpression of astrocyte proliferation and S100B proteins but not γ-aminobutyric acid A (GABAA) receptors. These results indicate that oral UR for 6 weeks can successfully attenuate mossy fiber sprouting, astrocyte proliferation, and S100B protein overexpression and increase neuronal survival in KA-induced epileptic rat hippocampus

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Section: Discussionmentioning

confidence: 65%

Neuroprotective Effect ofUncaria rhynchophyllain Kainic Acid-Induced Epileptic Seizures by Modulating Hippocampal Mossy Fiber Sprouting, Neuron Survival, Astrocyte Proliferation, and S100B Expression

Liu

Lin

Tang

et al. 2012

Evidence-Based Complementary and Alternative Medicine

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“…An autoradiography study using [ 3 H]-FMZ found decreases in both B max and K d in subregions of resected hippocampi following epilepsy surgery [5], again agreeing with the current study. In a previous study using ex vivo autoradiography in the post-KA SE rat model of TLE we found a decrease in the GABA A /cBZR density in hippocampal subfields but no change in receptor binding affinity (K d ) in epileptic animals six weeks following the SE [8]. Consistent with this, in this in vivo study at the same time point post-SE we found a decrease in B max for [ 18 F]-FMZ binding however, in contrast to our ex vivo study and previous work by Syvanen and colleagues [9], we also found an increase in binding affinity (1/K d V r ).…”

Section: Discussionmentioning

confidence: 69%

“…SE was induced using a repeated low-dose KA treatment protocol, adapted from that of Hellier et al [26], as previously described by our group [8], [27], which is associated with reduced animal mortality as compared to traditional single dose protocols. For this, eight male Wistar rats were injected intraperitoneally (i.p.)…”

Section: Methodsmentioning

confidence: 99%

“…This reduction in GABAergic neurotransmission may be caused by any or all of the following: loss of GABAergic interneurons, loss of GABA A receptors, or changes to GABA A receptor subunits, leading to alterations in receptor properties [2], [3], [4] and needs to be further investigated. Previous animal and human studies have shown decreased GABA A /central benzodiazepine receptor (GABA A /cBZR) density in structures important to seizure generation in the mesial temporal lobe [5], [6], [7], [8], [9].…”

Section: Introductionmentioning

confidence: 99%

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In Vivo Measurement of Hippocampal GABAA/cBZR Density with [18F]-Flumazenil PET for the Study of Disease Progression in an Animal Model of Temporal Lobe Epilepsy

et al. 2014

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PurposeImbalance of inhibitory GABAergic neurotransmission has been proposed to play a role in the pathogenesis of temporal lobe epilepsy (TLE). This study aimed to investigate whether [18F]-flumazenil ([18F]-FMZ) PET could be used to non-invasively characterise GABAA/central benzodiazepine receptor (GABAA/cBZR) density and affinity in vivo in the post-kainic acid status epilepticus (SE) model of TLE.MethodsDynamic [18F]-FMZ -PET scans using a multi-injection protocol were acquired in four male wistar rats for validation of the partial saturation model (PSM). SE was induced in eight male Wistar rats (10 weeks of age) by i.p. injection of kainic acid (7.5–25 mg/kg), while control rats (n = 7) received saline injections. Five weeks post-SE, an anatomic MRI scan was acquired and the following week an [18F]-FMZ PET scan (3.6–4.6 nmol). The PET data was co-registered to the MRI and regions of interest drawn on the MRI for selected structures. A PSM was used to derive receptor density and apparent affinity from the [18F]-FMZ PET data.Key FindingsThe PSM was found to adequately model [18F]-FMZ binding in vivo. There was a significant decrease in hippocampal receptor density in the SE group (p<0.01), accompanied by an increase in apparent affinity (p<0.05) compared to controls. No change in cortical receptor binding was observed. Hippocampal volume reduction and cell loss was only seen in a subset of animals. Histological assessment of hippocampal cell loss was significantly correlated with hippocampal volume measured by MRI (p<0.05), but did not correlate with [18F]-FMZ binding.SignificanceAlterations to hippocampal GABAA/cBZR density and affinity in the post-kainic acid SE model of TLE are detectable in vivo with [18F]-FMZ PET and a PSM. These changes are independent from hippocampal cell and volume loss. [18F]-FMZ PET is useful for investigating the role that changes GABAA/cBZR density and binding affinity play in the pathogenesis of TLE.

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“…SE was induced in 13 male Wistar rats (286 ± 4 g) as described before [11,12]. Briefly, by step-wise intraperitoneal (i.p.)…”

Section: Methodsmentioning

confidence: 99%

PET imaging of brain inflammation during early epileptogenesis in a rat model of temporal lobe epilepsy

et al. 2012

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BackgroundRecently, inflammatory cascades have been suggested as a target for epilepsy therapy. Positron emission tomography (PET) imaging offers the unique possibility to evaluate brain inflammation longitudinally in a non-invasive translational manner. This study investigated brain inflammation during early epileptogenesis in the post-kainic acid-induced status epilepticus (KASE) model with post-mortem histology and in vivo with [18F]-PBR111 PET.MethodsStatus epilepticus (SE) was induced (N = 13) by low-dose injections of KA, while controls (N = 9) received saline. Translocator protein (TSPO) expression and microglia activation were assessed with [125I]-CLINDE autoradiography and OX-42 immunohistochemistry, respectively, 7 days post-SE. In a subgroup of rats, [18F]-PBR111 PET imaging with metabolite-corrected input function was performed before post-mortem evaluation. [18F]-PBR111 volume of distribution (Vt) in volume of interests (VOIs) was quantified by means of kinetic modelling and a VOI/metabolite-corrected plasma activity ratio.ResultsAnimals with substantial SE showed huge overexpression of TSPO in vitro in relevant brain regions such as the hippocampus and amygdala (P < 0.001), while animals with mild symptoms displayed a smaller increase in TSPO in amygdala only (P < 0.001). TSPO expression was associated with OX-42 signal but without obvious cell loss. Similar in vivo [18F]-PBR111 increases in Vt and the simplified ratio were found in key regions such as the hippocampus (P < 0.05) and amygdala (P < 0.01).ConclusionBoth post-mortem and in vivo methods substantiate that the brain regions important in seizure generation display significant brain inflammation during epileptogenesis in the KASE model. This work enables future longitudinal investigation of the role of brain inflammation during epileptogenesis and evaluation of anti-inflammatory treatments.

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Changes in hippocampal GABAA/cBZR density during limbic epileptogenesis: Relationship to cell loss and mossy fibre sprouting

Cited by 23 publications

References 58 publications

Neuroprotective Effect ofUncaria rhynchophyllain Kainic Acid-Induced Epileptic Seizures by Modulating Hippocampal Mossy Fiber Sprouting, Neuron Survival, Astrocyte Proliferation, and S100B Expression

Neuroprotective Effect ofUncaria rhynchophyllain Kainic Acid-Induced Epileptic Seizures by Modulating Hippocampal Mossy Fiber Sprouting, Neuron Survival, Astrocyte Proliferation, and S100B Expression

In Vivo Measurement of Hippocampal GABAA/cBZR Density with [18F]-Flumazenil PET for the Study of Disease Progression in an Animal Model of Temporal Lobe Epilepsy

PET imaging of brain inflammation during early epileptogenesis in a rat model of temporal lobe epilepsy

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