Altered expression of GABA-A receptor subunits in the hippocampus of PTZ-kindled rats

Szyndler, Janusz; Maciejak, Piotr; Kołosowska, Karolina; Chmielewska, Natalia; Skórzewska, Anna; Daszczuk, Patrycja; Płaźnik, Adam

doi:10.1016/j.pharep.2017.07.008

Cited by 18 publications

(9 citation statements)

References 25 publications

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“…Additionally, albeit with tissue from a limited number of patients, we find evidence here that tonic inhibition may be altered by a number of clinical parameters, including age, seizures, levetiracetam, and type of cancer. Decreases in tonic inhibition (Pandit et al, 2013), or δ-subunit expression (Peng et al, 2004;Rajasekaran et al, 2010;Drexel et al, 2013;Wan et al, 2014;Szyndler et al, 2018), have been observed in the hippocampi of rodent epilepsy models, particularly in the granule cells of the dentate gyrus, perhaps consistent with the decreased tonic inhibition observed in patients with seizures in this study. Interestingly, the trend towards a decrease in tonic currents in rosehip cells may suggest a cell-type specific effect of seizures.…”

Section: Discussionsupporting

confidence: 84%

Tonic GABA_AReceptor-Mediated Currents of Human Cortical GABAergic Interneurons Vary Amongst Cell Types

et al. 2021

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Persistent anion conductances through GABA A receptors (GABA A R) are important modulators of neuronal excitability. However, it is currently unknown how the amplitudes of these currents vary amongst different cell types in the human neocortex, particularly amongst diverse GABAergic interneurons. We have recorded 101 interneurons in and near layer 1 from cortical tissue surgically resected from both male and female patients, visualised 84 of them and measured tonic GABA A R currents in 48 cells with an intracellular [Cl -] of 65 mM and in the presence of 5 µM GABA. We compare these tonic currents amongst five groups of interneurons divided by firing properties and four types of interneuron defined by axonal distributions; rosehip, neurogliaform, stalked-bouton, layers 2-3 innervating and a pool of other cells. Interestingly, the rosehip cell, a type of interneuron only described thus far in human tissue, and layers 2-3 innervating cells exhibit larger tonic currents than other layer 1 interneurons, such as neurogliaform and stalked-bouton cells; the latter two groups showing no difference. The positive allosteric modulators of GABA A Rs allopregnanolone and DS2 also induced larger current shifts in the rosehip and layer 2-3 innervating cells, consistent with higher expression of the δ-subunit of the GABA A R in these neurons. We have also examined how patient parameters, such as age, seizures, type of cancer and anticonvulsant treatment may alter tonic inhibitory currents in human neurons.The cell type specific differences in tonic inhibitory currents could potentially be used to selectively modulate cortical circuitry. Significance statementTonic currents through GABA A receptors are a potential therapeutic target for a number of neurological and psychiatric conditions. Here we show that these currents in human cerebral cortical GABAergic neurons display cell-type specific differences in their amplitudes 4 which implies differential modulation of their excitability. Additionally, we examine whether the amplitudes of the tonic currents measured in our study show any differences between patient populations, finding some evidence that age, seizures, type of cancer, and anticonvulsant treatment may alter tonic inhibition in human tissue. These results advance our understanding of how pathology affects neuronal excitability and could potentially be used to selectively modulate cortical circuitry.

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Section: Discussionsupporting

confidence: 84%

Tonic GABA_AReceptor-Mediated Currents of Human Cortical GABAergic Interneurons Vary Amongst Cell Types

et al. 2021

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“…Since the subunit's construction determines functional and pharmacological properties of the receptors, attenuation of the GABAergic neurotransmission in epileptic individuals might result, among others, from changes in the subunit composition of GABA A receptors. The α1 subunit is considered to be involved in epilepsy/seizures (Chuang and Reddy 2018;Greenfield 2013) and modifications in its expression were noted in different brain structures both in epileptic patients (Kanaumi et al 2006;Loup et al 2009) as well as in experimental animals (Brooks-Kayal et al 1998;Chen et al 2019;Szyndler et al 2018). Szyndler et al (2018) reported an increased α1 subunit expression in the hippocampus (i.e., in the CA1, CA3, and dentate gyrus) of fully PTZ-kindled animals that were sacrificed 48 h after the last PTZ treatment.…”

Section: Discussionmentioning

confidence: 99%

“…The α1 subunit is considered to be involved in epilepsy/seizures (Chuang and Reddy 2018;Greenfield 2013) and modifications in its expression were noted in different brain structures both in epileptic patients (Kanaumi et al 2006;Loup et al 2009) as well as in experimental animals (Brooks-Kayal et al 1998;Chen et al 2019;Szyndler et al 2018). Szyndler et al (2018) reported an increased α1 subunit expression in the hippocampus (i.e., in the CA1, CA3, and dentate gyrus) of fully PTZ-kindled animals that were sacrificed 48 h after the last PTZ treatment. Acute treatment with PTZ also potentiated the expression of this subunit but the effect was limited to the dentate gyrus only.…”

Section: Discussionmentioning

confidence: 99%

Anticonvulsant effect of pterostilbene and its influence on the anxiety- and depression-like behavior in the pentetrazol-kindled mice: behavioral, biochemical, and molecular studies

et al. 2021

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Rationale Pterostilbene is the 3,5-dimethoxy derivative of resveratrol with numerous beneficial effects including neuroprotective properties. Experimental studies revealed its anticonvulsant action in the acute seizure tests. Objectives The purpose of the present study was to evaluate the effect of pterostilbene in the pentetrazol (PTZ)–induced kindling model of epilepsy in mice as well as to assess some possible mechanisms of its anticonvulsant action in this model. Methods Mice were repeatedly treated with pterostilbene (50–200 mg/kg) and its effect on the development of seizure activity in the PTZ kindling was estimated. Influence of pterostilbene on the locomotor activity and anxiety- and depression-like behavior in the PTZ-kindled mice was also assessed. To understand the possible mechanisms of anticonvulsant activity of pterostilbene, γ-aminobutyric acid (GABA) and glutamate concentrations in the prefrontal cortex and hippocampus of the PTZ-kindled mice were measured using LC–MS/MS method. Moreover, mRNA expression of BDNF, TNF-α, IL-1β, IL-6, GABRA1A, and GRIN2B was determined by RT-qPCR technique. Results We found that pterostilbene at a dose of 200 mg/kg considerably reduced seizure activity but did not influence the locomotor activity and depression- and anxiety-like behavior in the PTZ-kindled mice. In the prefrontal cortex and hippocampus, pterostilbene reversed the kindling-induced decrease of GABA concentration. Neither in the prefrontal cortex nor hippocampus pterostilbene affected mRNA expression of IL-1β, IL-6, GABRA1A, and GRIN2B augmented by PTZ kindling. Pterostilbene at a dose of 100 mg/kg significantly decreased BDNF and TNF-α mRNA expression in the hippocampus of the PTZ-kindled mice. Conclusions Although further studies are necessary to understand the mechanism of anticonvulsant properties of pterostilbene, our findings suggest that it might be considered a candidate for a new antiseizure drug.

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“…5d; 16.00±2.48 vs 8.75±1.32, P=0.042, n=4) of epileptiform discharge after PTZ induction at a subconvulsive dose (30 mg/kg, i.p.) (Szyndler et al 2018;Taiwe et al 2016;Van Erum et al 2019). The coastline bursting index showed that there was no signi cant difference at baseline between N-G mice and N-G/RAGE -/mice before PTZ injection (Fig.…”

Section: Activation Of Hmgb1-rage May Affect the Ptz-induced Epileptiform Discharge In The Fl Modelmentioning

confidence: 93%

HMGB1-RAGE Pathway Contributes to the Abnormal Migration of Endogenous Subventricular Zone Neural Progenitors in an Experimental Model of Focal Microgyria

Mei

Huang

Chen³

et al. 2021

J Mol Neurosci

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Abnormal migration of subventricular zone (SVZ)-derived neural progenitor cells (SDNPs) is involved in the pathological and epileptic processes of focal cortical dysplasia (FCD), but the underlying mechanisms are still unclear. Recent studies have indicated that high mobility group box 1 (HMGB1)/receptor for advanced glycation end products (RAGE) is widely expressed in epileptic specimens of FCD, suggesting that the HMGB1-RAGE pathway may be involved in the pathological and/or epileptic processes of FCD. In the present study, by using Nestin-GFP tg/+ transgenic mice, we established a model of freezing lesion (FL), as described in our previous report. A "migrating stream", which was composed of GFP-Nestin + SDNPs, was derived from the SVZ region and migrated to the cortical FL area. We found that translocated HMGB1 and RAGE were expressed in cortical lesion in a clustered distribution pattern, which was especially obvious in the early stage of FL compared with the sham group. Interestingly, the number of GFP-Nestin + SDNPs within the migrating stream was signi cantly decreased when the HMGB1-RAGE pathway was blocked by an antagonist of RAGE or deletion of the RAGE gene. Moreover, the absence of RAGE also decreased the activity of pentylenetetrazol-induced cortical epileptiform discharge. In summary, this study provided experimental evidence that in the early stage of FL, the levels of extranuclear HMGB1 and its receptor RAGE were increased in cortical lesion in the FL model. Activation of the HMGB1-RAGE pathway may contribute to the abnormal migration of SDNPs and the hyperexcitability of cortical lesion in the FL model.

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Altered expression of GABA-A receptor subunits in the hippocampus of PTZ-kindled rats

Abstract: The pattern of changes observed in our study indicates that changes in tonic inhibition are involved in abnormal neuronal activity observed in PTZ model of epilepsy.

Cited by 18 publications

References 25 publications

Tonic GABA_AReceptor-Mediated Currents of Human Cortical GABAergic Interneurons Vary Amongst Cell Types

Tonic GABA_AReceptor-Mediated Currents of Human Cortical GABAergic Interneurons Vary Amongst Cell Types

Anticonvulsant effect of pterostilbene and its influence on the anxiety- and depression-like behavior in the pentetrazol-kindled mice: behavioral, biochemical, and molecular studies

HMGB1-RAGE Pathway Contributes to the Abnormal Migration of Endogenous Subventricular Zone Neural Progenitors in an Experimental Model of Focal Microgyria

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Altered expression of GABA-A receptor subunits in the hippocampus of PTZ-kindled rats

Abstract: The pattern of changes observed in our study indicates that changes in tonic inhibition are involved in abnormal neuronal activity observed in PTZ model of epilepsy.

Cited by 18 publications

References 25 publications

Tonic GABAAReceptor-Mediated Currents of Human Cortical GABAergic Interneurons Vary Amongst Cell Types

Tonic GABAAReceptor-Mediated Currents of Human Cortical GABAergic Interneurons Vary Amongst Cell Types

Anticonvulsant effect of pterostilbene and its influence on the anxiety- and depression-like behavior in the pentetrazol-kindled mice: behavioral, biochemical, and molecular studies

HMGB1-RAGE Pathway Contributes to the Abnormal Migration of Endogenous Subventricular Zone Neural Progenitors in an Experimental Model of Focal Microgyria

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Tonic GABA_AReceptor-Mediated Currents of Human Cortical GABAergic Interneurons Vary Amongst Cell Types

Tonic GABA_AReceptor-Mediated Currents of Human Cortical GABAergic Interneurons Vary Amongst Cell Types