Central deficiency of norepinephrine synthesis and norepinephrinergic neurotransmission contributes to seizure-induced respiratory arrest

Optogenetic activation of the serotonergic neural circuit between the dorsal raphe nucleus and pre-Bötzinger complex contributes to inhibition of seizure-induced respiratory arrest in the DBA/1 mouse SUDEP model

“…PTZ-evoked seizure model, PTZ was administered to non-primed DBA/1 mice of approximately 8 weeks of age. The two models were established just as we described previously 5-12 . TPH2-ChETA infected mice was established by viral delivery of pAAV-TPH2 PRO-ChETA-EYFP-WPRES-PAS with the control of promoter of TPH2 into the DR to express for 3 weeks and confirmed the expression of TPH2 -ChETA in DR by immunohistochemistry.…”

“…Aiming at the ICV surgery, an ICV guide cannula(O.D.I.41×I.D.O.0.25mm/M3.5,62004, RWD Life Science Inc.,China)was implanted into the right lateral ventricle (AP – 0.45 mm; ML – 1.0 mm; V-2.50 mm) to enable microinjections as we previously described 9,12 . The groups to test as follows: 1) Saline (IP) was administered 75 mins prior to PTZ (75mg/kg, IP) and 25% DMSO at (2 μl, at a rate of 0.5 μl/min ICV) 15 min prior to PTZ injection as controls.…”

“…PTZ-evoked seizure model, PTZ was administered to non-primed DBA/1 mice of approximately 8 weeks of age. The two models were established just as we described previously [5][6][7][8][9][10][11][12] . TPH2-ChETA to be significantly infected the 5-HT neurons in the DR from our group to modulate the balance between reward and aversion 13 .…”

“…The latest advancements of the pathogenesis of SUDEP demonstrated that cardiopulmonary dysfunction plays an important role in the occurrence of SUDEP [1][2][3][4][5] . Our previous findings showed that seizure-induced respiratory arrest (S-IRA) can 3 lead to the occurrence of SUDEP evoked by either acoustic stimulation or pentylenetetrazole (PTZ) in DBA/1 murine models [5][6][7][8][9][10][11][12] , and the incidence of S-IRA by acoustic stimulation or PTZ was significantly reduced by 5-Hydroxytryptophan (5-HTP), a precursor for serotonin synthesis in two models of SUDEP 5 . However, the target of 5-HTP-mediated reduction of S-IRA and SUDEP in the brain remains unclear and still needs to be further explored.…”

“…Meanwhile, administration of KET reversed the lower incidence of S-IRA by 5-HTP with producing only partly anticonvulsant effects, which suggested that 5-HT2AR in brainstem may be a specific target to prevent S-IRA and SUDEP. Furthermore, considering that 5-HT2AR located in the pre-Bötzinger complex which plays a key role in modulating respiration rhythm 12 , and that the incidence of S-IRA in DBA/1 mice can be significantly reduced by optogenetic activation of TPH2-ChR2 neurons in DR based on our previous findings, we further activated TPH2-ChETA neurons in the DR of DBA/1 mice to observe whether the suppression of S-IRA in PTZ injection model by photostimulating the DR depends on activating 5-HT2AR located in the pre-Bötzinger complex or not. It turned out that the lower incidence of S-IRA evoked by PTZ by optogenetic activation of TPH2-ChETA neurons in the DR was remarkably reversed by injection of KET into the pre-Bötzinger complex.…”