Authors :
Presenting Author: Benton Purnell, PhD – Rutgers University
Jayant Bhasin, BS – Rutgers University
Fabio Tescarollo, PhD – Rutgers University
Spencer Chen, PhD – Rutgers University
Hai Sun, MD, PhD – Rutgers University
Detlev Boison, PhD – Rutgers University
Rationale:
Sudden unexpected death in epilepsy (SUDEP) is a leading cause of epilepsy related mortality. Postictal respiratory arrest plays a leading role in SUDEP pathophysiology. It is not clear why some seizures precipitate fatal respiratory arrest, or why this respiratory arrest would begin after the seizure is over.
Seizures cause a surge in extracellular adenosine in the forebrain, excessive adenosine in the brainstem can suppress breathing, and experimental manipulation of adenosine signaling alters vulnerability to seizure-induced death. We hypothesize that excessive seizure-induced adenosine surging contributes to seizure-induced respiratory arrest. However, this hypothesis is based on the unchecked assumption that seizures cause adenosine surging in the brainstem. The goal of this investigation was to use a mouse model of seizure-induced respiratory arrest to determine whether: (1) seizures cause brainstem adenosine surging, (2) this adenosine surge peaks after the seizure is over, and (3) brainstem adenosine surging is different in fatal and non-fatal seizures.
Methods:
Wild type, adult, male, CD1 mice were given viral injections and instrumented with an optic fiber in the hippocampus and dorsal raphe. The viruses drove expression of fluorescent sensors for extracellular adenosine (AAV9-hSyn-Ado1.1m) and intracellular calcium (AAV9-Syn-jRGECO1a). After recovery (14 d), electroshock seizures were induced (n =19 at 15 mA, n = 2 at the 50 mA maximal electroshock current). Dual-sensor/dual-fiber photometry was used to monitor changes in extracellular adenosine and intracellular calcium in the hippocampus and dorsal raphe while breathing was recorded using whole body plethysmography.
Results:
Electroshock seizures caused an adenosine surge in both the forebrain (p < 0.001) and the brainstem (p = 0.001). An intracellular calcium surge preceded the adenosine surge regardless of whether the seizure was fatal in both brain areas (Hippocampus: non-fatal p < 0.001, fatal, p < 0.001; Brainstem: non-fatal p < 0.001, fatal, p < 0.001). The lag between the seizure and the adenosine surge in the brainstem was twice as long in fatal seizures (19.98 sec) compared to non-fatal seizures (9.73 sec). In the hippocampus, seizure-induced adenosine surging in non-fatal seizures was slower to peak (p = 0.021) and longer in duration (p = 0.049) compared to fatal seizures. Conversely, in the brainstem adenosine surging during fatal seizures was not faster to peak (p = 0.083) and was longer in duration relative to non-fatal seizures (p = 0.008). All ‘p’ values are from t-tests, unpaired or paired as appropriate.
Conclusions:
Our data indicate that seizures do cause a surge in extracellular adenosine in the brainstem. Seizure-induced adenosine surging in the brainstem can persist long after the seizure is over, particularly in fatal seizures. This observation may shed light on the enigmatic clinical observation that the respiratory arrest seen in SUDEP begins after the seizure is over. The significance of these findings is that they suggest that a lingering adenosine surge in the brainstem may contribute to the seizure-induced respiratory arrest seen in SUDEP.
Funding: NS103740 to D.B. and NS117792 to B.P.