Neural activity in the periaqueductal gray and other specific subcortical structures is enhanced when a selective serotonin reuptake inhibitor selectively prevents seizure‐induced sudden death in the DBA/1 mouse model of sudden unexpected death in epilepsy

Abstract

Objective Sudden unexpected death in epilepsy (SUDEP) is a critical issue in epilepsy, and DBA/1 mice are a useful animal model of this devastating epilepsy sequela. The serotonin hypothesis for SUDEP proposes that modifying serotonergic function significantly alters susceptibility to seizure‐induced respiratory arrest (S‐IRA). Agents that enhance serotonergic function, including a selective serotonin reuptake inhibitor, fluoxetine, selectively prevent S‐IRA in DBA/1 mice. This study examined fluoxetine‐induced changes in brain activity using manganese‐enhanced magnetic resonance imaging (MEMRI) to reveal sites in the DBA/1 mouse brain where fluoxetine acts to prevent S‐IRA. Methods DBA/1 mice were subjected to audiogenic seizures (Sz) after saline or fluoxetine (45 mg/kg, intraperitoneal) administration. Control DBA/1 mice received fluoxetine or saline, but Sz were not evoked. A previous MEMRI study established the regions of interest (ROIs) for Sz in the DBA/1 mouse brain, and the present study examined MEMRI differences in the ROIs of these mouse groups. Results The neural activity in several ROIs was significantly increased in fluoxetine‐treated DBA/1 mice that exhibited Sz but not S‐IRA when compared to the saline‐treated mice that exhibited both Sz and respiratory arrest. These structures included the periaqueductal gray (PAG), amygdala, reticular formation (sensorimotor‐limbic network), Kölliker‐Fuse nucleus, facial‐parafacial group (respiratory network), and pontine raphe. Of these ROIs, only the PAG showed significantly decreased neural activity with saline pretreatment when seizure‐induced respiratory arrest occurred as compared to saline treatment without seizure. Significance The PAG is known to play an important compensatory role for respiratory distress caused by numerous exigent situations in normal animals. The pattern of fluoxetine‐induced activity changes in the present study suggests that PAG may be the most critical target for fluoxetine's action to prevent seizure‐induced sudden death. These findings have potential clinical importance, because there is evidence of anomalous serotonergic function and PAG imaging abnormalities in human SUDEP.

Decreased Resting-State Functional Connectivity of Periaqueductal Gray in Temporal Lobe Epilepsy Comorbid With Migraine

“…As the activation of PAG and PPN both have a pain suppressing effect, the decreased FC between PAG and PPN may give rise to a reduced pain threshold underlying migraine occurrence in epilepsy. Neuroimaging study has shown decreased activity in PAG in animals with epileptic seizures (59). This is consistent with our previous findings that there is a continuing loss of vlPAG neurons in rats with chronic epilepsy and neurochemical lesion to PAG decreases the pain threshold in epileptic rats (26).…”

Epilepsy Benchmarks Area IV: Limit or Prevent Adverse Consequence of Seizures and Their Treatment Across the Life Span

“…52,53,55,56 Several studies have implicated brainstem cardiorespiratory centers as critical mediators of SUDEP and suggested that serotonin neurons are major contributors. 54 , [57][58][59][60] Other studies hypothesized intrinsic cardiac arrhythmia phenotypes as another SUDEP mechanism. Relevant to Dravet syndrome and SCN1A, cardiomyocytes differentiated from patient-derived induced pluripotent stem cells (iPSCs) have abnormal physiology, suggesting cardiac arrhythmias may contribute to SUDEP.…”

Scurrying to Understand Sudden Expected Death in Epilepsy: Insights From Animal Models

“…3,[15][16][17] Reduced periaqueductal gray-mediated cardiorespiratory compensatory mechanism. 18,19 Caffeine can prevent S-IRA through adenosine A 2A receptors 20 Lmx1b f/f/p mouse maximal electroshock (MES)-induced seizure model Increasing 5-HT or NE or both improves S-IRA and death. 21,22 Seizure severity and dysregulation of breathing after MES seizures in mice is increased during sleep and during light phase 23,24 SCN1A mutant Dravet syndrome mouse models Death can be prevented by mechanical ventilation and atropine.…”

“…67 An insufficiency in the periaqueductal gray-mediated cardiorespiratory compensatory mechanism which can be enhanced by fluoxetine may underlie the death of DBA/1 mice. 18,19 5-HT 2C receptor-null mutant mice are also susceptible to AGS and death. 68 Mice with a genetic deletion of 5-HT neurons in the central nervous system ( Lm1xb f/f/p ) show increased susceptibility to and mortality from chemically and electrically induced seizures.…”