Allopregnanolone augments epileptiform activity of an in-vitro mouse hippocampal preparation in the first postnatal week

Sharopov, Salim; Winkler, Paula; Uehara, Rie; Lombardi, Aniello; Halbhuber, Lisa; Okabe, Akihito; Luhmann, Heiko J.; Kilb, Werner

doi:10.1016/j.eplepsyres.2019.106196

Cited by 3 publications

(3 citation statements)

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“…In contrast to these reports of excitatory GABAergic actions, several in vitro studies also demonstrate that GABAergic stimulation can mediate inhibition already in early postnatal neurons (Agmon et al, 1996 ; Khalilov et al, 1999 ; Lamsa et al, 2000 ). The frequent observations that inhibition of GABA A receptors provoke epileptiform discharges in the immature CNS (Khalilov et al, 1999 ; Wells et al, 2000 ; Richter et al, 2010 ; Kolbaev et al, 2012 ; Sharopov et al, 2019 ) also suggest that GABA may mediate a net inhibitory effect in immature hippocampal and neocortical networks. However, depolarizing GABAergic responses has been suggested to significantly contribute to epilepsy in the immature CNS (Dzhala and Staley, 2003 ; Dzhala et al, 2005 ; Khalilov et al, 2005 ; Nardou et al, 2009 , 2013 ).…”

Section: Examples For Excitatory and Inhibitory Gabaergic Effects In The Immature Cnsmentioning

confidence: 97%

When Are Depolarizing GABAergic Responses Excitatory?

Kilb

2021

Front. Mol. Neurosci.

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The membrane responses upon activation of GABA(A) receptors critically depend on the intracellular Cl− concentration ([Cl−]i), which is maintained by a set of transmembrane transporters for Cl−. During neuronal development, but also under several pathophysiological conditions, the prevailing expression of the Cl− loader NKCC1 and the low expression of the Cl− extruder KCC2 causes elevated [Cl−]i, which result in depolarizing GABAergic membrane responses. However, depolarizing GABAergic responses are not necessarily excitatory, as GABA(A) receptors also reduces the input resistance of neurons and thereby shunt excitatory inputs. To summarize our knowledge on the effect of depolarizing GABA responses on neuronal excitability, this review discusses theoretical considerations and experimental studies illustrating the relation between GABA conductances, GABA reversal potential and neuronal excitability. In addition, evidences for the complex spatiotemporal interaction between depolarizing GABAergic and glutamatergic inputs are described. Moreover, mechanisms that influence [Cl−]i beyond the expression of Cl− transporters are presented. And finally, several in vitro and in vivo studies that directly investigated whether GABA mediates excitation or inhibition during early developmental stages are summarized. In summary, these theoretical considerations and experimental evidences suggest that GABA can act as inhibitory neurotransmitter even under conditions that maintain substantial depolarizing membrane responses.

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Section: Examples For Excitatory and Inhibitory Gabaergic Effects In The Immature Cnsmentioning

confidence: 97%

When Are Depolarizing GABAergic Responses Excitatory?

Kilb

2021

Front. Mol. Neurosci.

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“…There are studies which show the anticonvulsant effect of ALLO in an immature brain. Sharopov et al (99) examined the impact of ALLO on epileptiform activity in an in-toto hippocampus preparation of early postnatal mice (postnatal days 4-7). It was found that the neurosteroid, through a positive modulation of GABA-A receptors, did not show any impact on ictal-like epileptiform activity, however, an increase in interictal epileptiform events was observed.…”

Section: Neurosteroids and Seizure Activity In The Pediatric Populatimentioning

confidence: 99%

“…It was found that the neurosteroid, through a positive modulation of GABA-A receptors, did not show any impact on ictal-like epileptiform activity, however, an increase in interictal epileptiform events was observed. Additionally, based on studies using a patch-clamp, it was determined that ALLO prolonged the decay of GABAergic postsynaptic currents, but did not result in changes in the case of tonic GABAergic currents, which could result in an increase in the neuronal excitability of an immature brain ( 99 ).On the other hand, in the case of in vivo studies, results by Dhir and Chopra ( 13 ) should be taken into consideration. They examined the effects of a ALLO in 9-day-old rat neonates against seizures induced by kainic acid, pentylenetetrazol or 4-aminopyridine.…”

Section: Neurosteroids and Seizure Activity In The Pediatric Populatimentioning

confidence: 99%

Neurosteroids and Seizure Activity

2020

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Still circa 25% to 30% of patients with epilepsy cannot be efficiently controlled with available antiepileptic drugs so newer pharmacological treatment options have been continuously searched for. In this context, a group of endogenous or exogenous neurosteroids allosterically positively modulating GABA-A receptors may offer a promising approach. Among endogenous neurosteroids synthesized in the brain, allopregnanolone or allotetrahydrodeoxycorticosterone have been documented to exert anticonvulsant activity in a number of experimental models of seizures-pentylenetetrazol-, bicuculline-pilocarpine-, or 6 Hz-induced convulsions in rodents. Neurosteroids can also inhibit fully kindled seizures and some of them have been reported to counteract maximal electroshock-induced convulsions. An exogenous neurosteroid, alphaxalone, significantly elevated the threshold for maximal electroconvulsions in mice but it did not potentiate the anticonvulsive action of a number of conventional antiepileptic drugs against maximal electroshock-induced seizures. Androsterone not only elevated the threshold but significantly enhanced the protective action of carbamazepine, gabapentin and phenobarbital against maximal electroshock in mice, as well. Ganaxolone (a 3betamethylated analog of allopregnanolone) needs special consideration for two reasons. First, it performed better than conventional antiepileptic drugs, diazepam or valproate, in suppressing convulsive and lethal effects of pentylenetetrazol in pentylenetetrazol-kindled mice. Second, ganaxolone has been evaluated in the randomized, double-blind, placebocontrolled phase 2 trial in patients with intractable partial seizures, taking maximally 3 antiepileptic drugs. The initial results indicate that add-on therapy with ganaxolone resulted in reduced seizure frequency with adverse effect being mainly mild to moderate. Possibly, ganaxolone may be also considered against catamenial seizures. Some positive effects of ganaxolone as an adjuvant were also observed in children with refractory seizures and its use may also prove efficient for the management of neonatal seizures associated with hypoxic injury. Neurosteroids positively modulating GABA-A receptor complex exert anticonvulsive activity in many experimental models of seizures. Their interactions with antiepileptic drugs seem ambiguous in mice. Initial clinical data indicate that ganaxolone may provide a better seizure control in patients with drug-resistant epilepsy.

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Enhancing GABAergic Tonic Inhibition Reduces Seizure-Like Activity in the Neonatal Mouse Hippocampus and Neocortex

Liddiard,

Suryavanshi,

Glykys

2024

J. Neurosci.

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Around one-third of neonatal seizures do not respond to first-line anticonvulsants, including phenobarbital, which enhances phasic inhibition. Whether enhancing tonic inhibition decreases seizure-like activity in the neonate when GABA is mainly depolarizing at this age is unknown. We evaluated if increasing tonic inhibition using THIP (4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol, Gaboxadol), a δ-subunit-selective GABAAreceptor agonist, decreases seizure-like activity in neonatal C57BL/6J mice (postnatal day P5-8, both sexes) using acute brain slices. Whole-cell patch-clamp recordings showed that THIP enhanced GABAergic tonic inhibitory conductances in layer V neocortical and CA1 pyramidal neurons and increased their rheobase without altering sEPSCs characteristics. Two-photon calcium imaging demonstrated that enhancing the activity of extrasynaptic GABAARs decreased neuronal firing in both brain regions. In the 4-aminopyridine and the Low-Mg2+model of pharmacoresistant seizures, THIP reduced epileptiform activity in the neocortex and CA1 hippocampal region of neonatal and adult brain slices in a dose-dependent manner. We conclude that neocortical layer V and CA1 pyramidal neurons have tonic inhibitory conductances, and when enhanced, they reduce neuronal firing and decrease seizure-like activity. Therefore, augmenting tonic inhibition could be a viable approach for treating neonatal seizures.Significance StatementNeonatal seizures occur in roughly 1-3/1000 term births and 10-fold more frequently in preterm neonates. Around 30-50% of neonatal seizures resist current treatments, and drug resistance often develops if diagnosis and treatment are delayed, for example, in underserved areas. There has been no significant improvement in treating neonatal seizures for nearly 50 years, especially for patients in whom pharmacoresistance develops. Our results show that enhancing tonic inhibition in neonatal mice, a developmental age when GABA mainly depolarizes, decreases neuronal firing and epileptiform activityin vitro. Our results suggest that augmenting tonic inhibition could be an alternative treatment for neonatal seizures, especially in pharmacy-resistant ones.

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Allopregnanolone augments epileptiform activity of an in-vitro mouse hippocampal preparation in the first postnatal week

Cited by 3 publications

References 81 publications

When Are Depolarizing GABAergic Responses Excitatory?

When Are Depolarizing GABAergic Responses Excitatory?

Neurosteroids and Seizure Activity

Enhancing GABAergic Tonic Inhibition Reduces Seizure-Like Activity in the Neonatal Mouse Hippocampus and Neocortex

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