Dorsal raphe nucleus to pre-Bötzinger complex serotonergic neural circuit is involved in seizure-induced respiratory arrest

Ma, HaiXiang; Yu, Qian; Shen, Yue; Lian, XiTing; Gu, LeYuan; Wang, Yuling; Xu, Qianfan; Han, Lu; Zhao, Hong; Zeng, Chang; Nagayasu, Kazuki; Zhang, Honghai

doi:10.1016/j.isci.2022.105228

Cited by 9 publications

(7 citation statements)

References 49 publications

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“…In the current study, we observed that stimulating the function of 5-HT 2A receptors relieves S-IRA in DBA/1 mice, consistent with a previous study using an electroshock model [20]. Another study also found that the reduction of S-IRA evoked by selective stimulation of 5-HT signaling was blocked by a 5-HT 2 antagonist in DBA/1 mice [43]. If the S-IRAsuppressing effect of the 5-HT 2A agonist TCB-2 were mediated by its action in the medullary respiratory center to augment breathing, we would expect that activation of 5-HT 1A , 5-HT 2B or 5-HT 7 receptors also reduced S-IRA in DBA/1 mice, as stimulation of these receptors was shown to promote breathing [34,35].…”

Section: Plos Onesupporting

confidence: 92%

5-HT receptors exert differential effects on seizure-induced respiratory arrest in DBA/1 mice

Pan,

Tan,

Guo

et al. 2024

PLoS ONE

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Both clinical and animal studies demonstrated that seizure-induced respiratory arrest (S-IRA) contributes importantly to sudden unexpected death in epilepsy (SUDEP). It has been shown that enhancing serotonin (5-HT) function relieves S-IRA in animal models of SUDEP, including DBA/1 mice. Direct activation of 5-HT3 and 5-HT4 receptors suppresses S-IRA in DBA/1 mice, indicating that these receptors are involved in S-IRA. However, it remains unknown if other subtypes of 5-HT receptors are implicated in S-IRA in DBA/1 mice. In this study, we investigated the action of an agonist of the 5-HT1A (8-OH-DPAT), 5-HT2A (TCB-2), 5-HT2B (BW723C86), 5-HT2C (MK-212), 5-HT6 (WAY-208466) and 5-HT7 (LP-211) receptor on S-IRA in DBA/1 mice. An agonist of the 5-HT receptor or a vehicle was intraperitoneally administered 30 min prior to acoustic simulation, and the effect of each drug/vehicle on the incidence of S-IRA was videotaped for offline analysis. We found that the incidence of S-IRA was significantly reduced by TCB-2 at 10 mg/kg (30%, n = 10; p < 0.01, Fisher’s exact test) but was not altered by other agonists compared with the corresponding vehicle controls in DBA/1 mice. Our data demonstrate that 5-HT2A receptors are implicated in S-IRA, and 5-HT1A, 5-HT2B, 5-HT2C, 5-HT6 and 5-HT7 receptors are not involved in S-IRA in DBA/1 mice.

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Section: Plos Onesupporting

confidence: 92%

5-HT receptors exert differential effects on seizure-induced respiratory arrest in DBA/1 mice

Pan,

Tan,

Guo

et al. 2024

PLoS ONE

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“…While we have not studied the effect of seizures on chemosensory neurons of the raphe nucleus, agonists for serotonin receptors (a key raphe neurotransmitter) have a protective effect in blocking seizure-induced SUDEP in DBA mice (Faingold et al, 2011 ; Ma et al, 2022 ) and mice with genetic deletion of serotonin neurons (Buchanan et al, 2014 ). Raphe neurons project to the RTN (Wu et al, 2019 ) and the pre-Bötzinger complex (Ma et al, 2022 ) and contribute to chemosensory responses in these nuclei. Thus, activation of serotonin receptors could help to compensate for the weakened responses of the chemosensitive RTN neurons and enhance the stimulatory effect of CO 2 on breathing (Mulkey et al, 2007 ; Wu et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Neural correlate of reduced respiratory chemosensitivity during chronic epilepsy

Bhandare,

Dale

2023

Front. Cell. Neurosci.

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While central autonomic, cardiac, and/or respiratory dysfunction underlies sudden unexpected death in epilepsy (SUDEP), the specific neural mechanisms that lead to SUDEP remain to be determined. In this study, we took advantage of single-cell neuronal Ca2+ imaging and intrahippocampal kainic acid (KA)-induced chronic epilepsy in mice to investigate progressive changes in key cardiorespiratory brainstem circuits during chronic epilepsy. Weeks after induction of status epilepticus (SE), when mice were experiencing recurrent spontaneous seizures (chronic epilepsy), we observed that the adaptive ventilatory responses to hypercapnia were reduced for 5 weeks after SE induction with its partial recovery at week 7. These changes were paralleled by alterations in the chemosensory responses of neurons in the retrotrapezoid nucleus (RTN). Neurons that displayed adapting responses to hypercapnia were less prevalent and exhibited smaller responses over weeks 3–5, whereas neurons that displayed graded responses to hypercapnia became more prevalent by week 7. Over the same period, chemosensory responses of the presympathetic rostral ventrolateral medullary (RVLM) neurons showed no change. Mice with chronic epilepsy showed enhanced sensitivity to seizures, which invade the RTN and possibly put the chemosensory circuits at further risk of impairment. Our findings establish a dysfunctional breathing phenotype with its RTN neuronal correlate in mice with chronic epilepsy and suggest that the assessment of respiratory chemosensitivity may have the potential for identifying people at risk of SUDEP.

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“…Although several antiseizure medications can reduce audiogenic seizures, adding validity to the models, 34 other drugs, including selective serotonin reuptake inhibitors, demonstrate a significant effect on seizure severity and SIRA in DBA mice. 28,35 Many studies have outlined an inherent dysfunction of the serotonergic system in DBA mice that might predispose mice to peri-ictal respiratory arrest. 36,37 Although this is observed in SUDEP cases and has suggested the possibility that serotonergically acting drugs can target SUDEP, the latter have no validated effect in epilepsy patients, 38 other than a small decrease in O 2 saturation.…”

Section: Rodent Models Of Sudepmentioning

confidence: 99%

“…Additionally, as fatal apnea in DBA mice is observed during the tonic phase of the seizure, any evaluation of novel pharmacological interventions affecting SIRA risk should also consider that a potential effect on seizure severity may ultimately be responsible. Although several antiseizure medications can reduce audiogenic seizures, adding validity to the models, 34 other drugs, including selective serotonin reuptake inhibitors, demonstrate a significant effect on seizure severity and SIRA in DBA mice 28,35 . Many studies have outlined an inherent dysfunction of the serotonergic system in DBA mice that might predispose mice to peri‐ictal respiratory arrest 36,37 .…”

Section: Rodent Models Of Sudepmentioning

confidence: 99%

Are we there yet? A critical evaluation of sudden and unexpected death in epilepsy models

Smith,

Richerson,

Kouchi

et al. 2023

Epilepsia

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Although animal models have helped to elaborate meaningful hypotheses about the pathophysiology of Sudden Unexpected Death in Epilepsy (SUDEP), specific prevention strategies are still lacking, potentially reflecting the limitations of these models and the intrinsic difficulties of investigating SUDEP. The interpretation of pre‐clinical data and their translation to diagnostic and therapeutic developments in patients thus require a high level of confidence in their relevance to model the human situation.Preclinical models of SUDEP models are heterogeneous and range from rodent and non‐rodent species. A critical aspect is whether the animals have isolated seizures exclusively induced by a specific trigger, such models where seizures are elicited by electrical stimulation or pharmacological intervention or DBA mouse strains, or whether they suffer from epilepsy with spontaneous seizures, with or without spontaneous SUDEP, either of non‐genetic epilepsy etiology or of genetically‐based developmental and epileptic encephalopathies. All these models have advantages and potential disadvantages, but it is important to be aware of these limitations to interpret data appropriately in a translational perspective. The majority of models with spontaneous seizures are of a genetic basis whereas SUDEP cases with a genetic basis represent only a small proportion of the total number. In almost all models, cardio‐respiratory arrest occurs during the course of the seizure, contrary to that in patients observed at the time of death, potentially raising the issue of whether we are studying models of SUDEP or models of peri‐seizure death. However, some of these limitations are impossible to avoid and can in part be dependent on specific features of SUDEP, which may be difficult to model. Several preclinical tools are available to address certain gaps in SUDEP pathophysiology, which can be used to further validate current preclinical models.

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Dorsal raphe nucleus to pre-Bötzinger complex serotonergic neural circuit is involved in seizure-induced respiratory arrest

Cited by 9 publications

References 49 publications

5-HT receptors exert differential effects on seizure-induced respiratory arrest in DBA/1 mice

5-HT receptors exert differential effects on seizure-induced respiratory arrest in DBA/1 mice

Neural correlate of reduced respiratory chemosensitivity during chronic epilepsy

Are we there yet? A critical evaluation of sudden and unexpected death in epilepsy models

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