Decreased serotonin synthesis is involved in seizure-induced respiratory arrest in DBA/1 mice

A known cause of seizure-induced respiratory arrest is the deficiency in serotonergic neurotransmission. Tryptophan hydroxylase-2 (TPH2) is the rate-limiting enzyme of central serotonin (5-hydroxytryptamine) synthesis which converts l-tryptophan to 5-hydroxytryptophan. A recent study revealed a reduction in TPH2 protein expression in the brainstems of DBA/1 mice that developed recurrent seizure-induced respiratory arrest, whereas the activity of this protein was unexplored. Thus this study aims to investigate the association between intrinsic 5-hydroxytryptamine synthesis in the brainstem and the susceptibility for sudden unexpected death in epilepsy in DBA/1 mice. The effect of LY393558, a potent 5-hydroxytryptamine reuptake inhibitor with 5-HT1B/1D receptor antagonist properties, on seizure-induced respiratory arrest evoked by acoustic stimulation was also examined in DBA/1 mice. ELISA results showed significantly decreased TPH2 activity in the brainstems of untreated DBA/1 mice than that of C57BL/6J mice. Moreover, the concentrations of 5-hydroxytryptamine, 5-hydroxytryptophan and 5-HIAA in the brainstems of DBA/1 mice with or without acoustic stimulation were significantly lower than that of C57BL/6J mice. Acute administration of LY393558 also significantly reduced seizure-induced respiratory arrest in DBA/1 mice. These observations provide novel evidences for the hypothesis that 5-hydroxytryptamine deficiency might be a potential cause of seizure-induced respiratory arrest.