The intrinsic clock of the hippocampal subfield CA3 rescues limbic seizures in a biohybrid graft-host interaction in vitro

Abstract

Hippocampal dysfunction is the hallmark of mesial temporal lobe epilepsy (MTLE), the most common epileptic syndrome in adults and the most often refractory to medical therapy. Deep brain stimulation (DBS) may ameliorate drug-refractory MTLE, but it still cannot guarantee a seizure-free life. One major drawback is that the stimulation policy is informed by trial-and-error rather than by the operating mode of the brain. Thus, optimizing DBS parameters is still an unmet clinical need. Here, we propose the deployment of hippocampal interictal activity in a biohybrid approach to control limbic ictogenesis. Specifically, an electronic bridge establishes a graft-host interaction between the hippocampal subfield CA3 (graft) and the parahippocampal cortex (CTX - host) of distinct rodent brain slices, both treated with 4-aminopyridine; the electronic bridge relays the graft interictal events to the host via electrical pulses. We show that interictal activity generated by the graft CA3 controls limbic ictogenesis in the host CTX even in the absence of feedback from it, thus likely reflecting an intrinsic anti-ictogenic clock of this brain region. This work opens a translational perspective for MTLE treatment via biohybrid neuroprostheses relying on the intrinsic clock of incorporated hippocampal cells.