The pharmacological assessment of GABA_A receptor activation in experimental febrile seizures in mice

Abstract

Hyperthermia-induced febrile seizures (FSs) are the most common seizures during childhood, and prolonged complex FSs can result in the development of epilepsy. Currently, GABA_A receptor modulators such as benzodiazepines and barbiturates are used as medications for FSs with the aim of enhancing GABA-mediated inhibition of neuronal activity. However, it is still up for debate whether these enhancers of GABAergic neurotransmission could depolarize immature neurons with relatively higher levels of the intracellular Cl^- in the developing brain during FSs. Here, we performed simultaneous video-local field potential (LFP) monitoring to determine whether benzodiazepines and barbiturates affect the phenotypes of FSs in postnatal day 11 (P11) and P14 mice. We found that low-dose administration of diazepam decreased the incidence of clonic seizures at P11. We also found that high-dose administration of diazepam and pentobarbital exacerbated the behavioral and electrophysiological phenotypes of the induction phase of experimental FSs at P11 but not at P14. We further found that the deteriorated phenotypes at P11 were suppressed when Na⁺K⁺2Cl^- co-transporter isoform 1 (NKCC1), which mediates Cl^- influx, was blocked by treatment with the diuretic bumetanide. Though our findings do not exclude the involvement of sedation effect of high-dose GABA_A receptor modulators in worsening experimental FSs at P11, pharmacological enhancement of GABAergic signaling could aggravate seizure activity in the early phase of FSs.

Significance Statement Febrile seizures are the most common neurological disorder in children. For the treatment of febrile seizures, GABA_A receptor modulators are generally used and successfully supress seizures in most cases. However, it is still up for debate whether these drugs could depolarize immature neurons in the developing brain. Here, using a mouse model of febrile seizures, we show that high-dose GABA_A receptor modulators exacerbate the behavioral and electrophysiological phenotypes of complex febrile seizures at postnatal day 11 but not at 14. We further found that the Na⁺K⁺2Cl^- co-transporter isoform 1 blocker bumetanide suppresses the phenotypes deteriorated by GABA_A receptor modulators. Thus, our findings suggest high-dose GABA_A receptor modulators possibly activate immature neurons.