Abstract
BACKGROUND: Preferential activation of Acid-sensing ion channel 1a (ASIC1a) by acidosis promotes seizure termination. Studies have found that CO(2) can reduce neuronal excitability and inhibit seizure activity. Dravet syndrome (DS) is a severe and catastrophic form of epilepsy primarily caused by monoallelic loss-of-function mutations in the SCN1A gene. Patients with DS suffer from frequent seizures, which can be triggered by fever and are often resistant to anti-seizure medications. Thus, this study aimed to explore the effect of inhaling 5% CO(2) and activating ASIC1a against hyperthermia-induced seizures in a mouse model of DS (Scn1a(+/-)). METHODS: Mice aged postnatal day 18-28 were divided into four groups: wild type (WT) + air, Scn1a(+/-) + air, WT + CO(2), and Scn1a(+/-) + CO(2). Hyperthermia-induced seizures were performed 60 min after gas inhalation. Neuronal damage was assessed using Nissl staining, whereas ASIC1a expression was evaluated through Western blot and immunofluorescence staining. RESULTS: In the hyperthermia-induced seizure tests, no seizures occurred in WT mice. All mice in the Scn1a(+/-) + air groups experienced seizures. In the Scn1a(+/-) + CO(2) group, all but one mouse had seizures. CO(2) inhalation shortened the duration of seizures in Scn1a(+/-) mice, improved electroencephalogram discharge patterns, and reduced neuronal damage in the hippocampus. The ASIC1a protein was mainly expressed in hippocampal neurons, with minor expression observed in astrocytes. The level of hippocampal ASIC1a increased in the Scn1a(+/-) + CO(2) mice. CONCLUSIONS: After CO(2) inhalation, the expression of the ASIC1a protein in the hippocampus increased, the duration of hyperthermia-induced seizures was reduced in Scn1a(+/-) mice, and the damage to hippocampal neurons was alleviated.