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 epileps

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.

journal_name

Epilepsia

journal_title

Epilepsia

authors

Kommajosyula SP,Faingold CL

doi

10.1111/epi.14759

subject

Has Abstract

pub_date

2019-06-01 00:00:00

pages

1221-1233

issue

6

eissn

0013-9580

issn

1528-1167

journal_volume

60

pub_type

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