Tonic GABAA Receptors as Potential Target for the Treatment of Temporal Lobe Epilepsy

Schipper, Sandra; Aalbers, Marlien W.; Rijkers, Kim; Swijsen, Ann; Rigo, Jean-Michel; Hoogland, Govert; Vles, Johan S.H.

doi:10.1007/s12035-015-9423-8

Cited by 46 publications

(28 citation statements)

References 138 publications

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“…Given the crucial role of inhibitory synapses in regulating both neuronal excitability and excitatory synaptic plasticity, changes in GABAergic synaptic efficacy can have important functional and pathological consequences [ 56 ]. As in excitatory neurotransmission, changes in GABA ( γ -aminobutyric acid) receptor composition, expression, cellular distribution, and function, therefore, have profound consequences for neural excitability, and they are associated with the etiology of several neurological and mental diseases, including epilepsy [ 57 ].…”

Section: Is the Gabaergic Synaptic Plasticity Implicated In The Epmentioning

confidence: 99%

Plasticity of Hippocampal Excitatory-Inhibitory Balance: Missing the Synaptic Control in the Epileptic Brain

2016

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Synaptic plasticity is the capacity generated by experience to modify the neural function and, thereby, adapt our behaviour. Long-term plasticity of glutamatergic and GABAergic transmission occurs in a concerted manner, finely adjusting the excitatory-inhibitory (E/I) balance. Imbalances of E/I function are related to several neurological diseases including epilepsy. Several evidences have demonstrated that astrocytes are able to control the synaptic plasticity, with astrocytes being active partners in synaptic physiology and E/I balance. Here, we revise molecular evidences showing the epileptic stage as an abnormal form of long-term brain plasticity and propose the possible participation of astrocytes to the abnormal increase of glutamatergic and decrease of GABAergic neurotransmission in epileptic networks.

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Section: Is the Gabaergic Synaptic Plasticity Implicated In The Epmentioning

confidence: 99%

Plasticity of Hippocampal Excitatory-Inhibitory Balance: Missing the Synaptic Control in the Epileptic Brain

2016

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“…Asynchronous GABA release, GABA spillover and tonic inhibition are known to modulate the input-output behavior of single neurons by shunting excitatory currents and hyperpolarizing the membrane potential and therefore have a protective role in epilepsy [ 46 , 47 ]. A decrease in tonic inhibition was identified in some animal models of epilepsy (see [ 48 , 49 ] for review), including Syn II KO and TKO mice [ 22 , 23 ]. The protective role of tonic inhibition from hyperexcitability is further strengthened by the tonic stimulation of presynaptic GABA B Rs by extracellular GABA.…”

Section: Discussionmentioning

confidence: 99%

Impaired GABAB-mediated presynaptic inhibition increases excitatory strength and alters short-term plasticity in synapsin knockout mice

et al. 2017

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Synapsins are a family of synaptic vesicle phosphoproteins regulating synaptic transmission and plasticity. SYN1/2 genes are major epilepsy susceptibility genes in humans. Consistently, synapsin I/II/III triple knockout (TKO) mice are epileptic and exhibit severe impairments in phasic and tonic GABAergic inhibition that precede the appearance of the epileptic phenotype. These changes are associated with an increased strength of excitatory transmission that has never been mechanistically investigated. Here, we observed that an identical effect in excitatory transmission could be induced in wild-type (WT) Schaffer collateral-CA1 pyramidal cell synapses by blockade of GABAB receptors (GABABRs). The same treatment was virtually ineffective in TKO slices, suggesting that the increased strength of the excitatory transmission results from an impairment of GABAB presynaptic inhibition. Exogenous stimulation of GABABRs in excitatory autaptic neurons, where GABA spillover is negligible, demonstrated that GABABRs were effective in inhibiting excitatory transmission in both WT and TKO neurons. These results demonstrate that the decreased GABA release and spillover, previously observed in TKO hippocampal slices, removes the tonic brake of presynaptic GABABRs on glutamate transmission, making the excitation/inhibition imbalance stronger.

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“…In an earlier study we showed that quercetin has anticonvulsant activity in acute and chronic models of chemical kindling induced by pentylenetetrazole (PTZ) [15,18]. More recently, Schipper et al suggested that tonic GABA A receptors are a potential target for the treatment of TLE [21]. The aim of this study was to determine the molecular mechanism of the antiseizure effects of quercetin on the expression of the GABA A a5 receptor gene in a KA model of epilepsy in mice.…”

Section: Introductionmentioning

confidence: 91%

The effects of quercetin on the gene expression of the GABAA receptor α5 subunit gene in a mouse model of kainic acid-induced seizure

et al. 2016

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The flavonoid quercetin has recently been reported to have neuroprotective effects, and the role of the gamma-aminobutyric acid A alpha 5 subunit (GABA α5) receptor has been determined in some nervous system disorders. The aim of this study was to identify the molecular mechanism of the effect of quercetin administered at anticonvulsive doses on the expression of the GABA α5 receptor gene in kainic acid (KA)-induced seizures in mice. The experimental animals were divided into four groups: control, KA, and KA + quercetin at 50 or 100 mg/kg, respectively. The results showed a dose-dependent reduction in the behavioral seizure score with quercetin pre-treatment in the KA mouse model. Two hours after the end of the 7-day treatment regimen, expression of the GABA α5 receptor gene in the hippocampus was found to be increased in the KA group, but this increase was reduced in the KA + quercetin 50 or 100 mg/kg treatment groups. These results suggest that expression of the GABA α5 receptor could be a mechanism for reducing seizure severity or may be a marker of seizure severity. Further studies are necessary to clarify quercetin's mechanism of action and the relation of GABA α5 receptor gene expression to seizure severity.

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Tonic GABAA Receptors as Potential Target for the Treatment of Temporal Lobe Epilepsy

Cited by 46 publications

References 138 publications

Plasticity of Hippocampal Excitatory-Inhibitory Balance: Missing the Synaptic Control in the Epileptic Brain

Plasticity of Hippocampal Excitatory-Inhibitory Balance: Missing the Synaptic Control in the Epileptic Brain

Impaired GABAB-mediated presynaptic inhibition increases excitatory strength and alters short-term plasticity in synapsin knockout mice

The effects of quercetin on the gene expression of the GABAA receptor α5 subunit gene in a mouse model of kainic acid-induced seizure

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