Biology subjects

Panuccio, G.

Publications and source records attributed to Panuccio, G..

3 recordsLinked to original sources

bioRxiv2023

Biohybrid restoration of the hippocampal loop re-establishes the non-seizing state in an in vitro model of limbic seizures

ObjectiveThe compromise of the hippocampal loop is a hallmark of mesial temporal lobe epilepsy (MTLE), the most frequent epileptic syndrome in the adult population and the most often refractory to medical therapy. Hippocampal sclerosis is found in >50% of drug-refractory MTLE patients and primarily involves the CA1, consequently disrupting the hippocampal output to the entorhinal cortex (EC). Closed-loop deep brain stimulation (DBS) is the latest frontier to improve drug-refractory MTLE; however, current approaches do not restore the functional connectivity of the hippocampal loop, they are designed by trial-and-error and heavily rely on seizure detection or prediction algorithms. The objective of this study is to evaluate the anti-ictogenic efficacy and robustness of an artificial bridge restoring the dialog between hippocampus and EC. ApproachIn mouse hippocampus-EC slices treated with 4-aminopyridine and in which the Schaffer Collaterals are severed, we established an artificial bridge between hippocampus and EC wherein interictal discharges originating in the CA3 triggered stimulation of the subiculum so to entrain EC networks. Combining quantification of ictal activity with tools from information theory, we addressed the efficacy of the bridge in controlling ictogenesis and in restoring the functional connectivity of the hippocampal loop. Main resultsThe bridge significantly decreased or even prevented ictal activity and proved robust to failure; when operating at 100% of its efficiency (i.e., delivering a pulse upon each interictal event), it recovered the functional connectivity of the hippocampal loop to a degree similar to what measured in the intact circuitry. The efficacy and robustness of the bridge stem in mirroring the adaptive properties of the CA3, which acts as biological neuromodulator. Significance. This work is the first stepping stone toward a paradigm shift in the conceptual design of stimulation devices for epilepsy treatment, from function control to functional restoration of the salient brain circuits.

neuroscience↗

bioRxiv2023

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

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.

neuroscience↗

bioRxiv2023

Developing hippocampal spheroids model ictogenesis and epileptogenesis

Three-dimensional (3D) neural cell cultures inherently lend themselves to high-throughput network electrophysiology studies addressing brain function in health and disease in a more realistic architectural complexity than two-dimensional neural networks. Epilepsy is the emblem of brain network disorders, as it reflects aberrant circuit reorganization and hyper-synchronization, resulting in sudden and uncontrolled electrical discharges (seizures). Modeling the features of epilepsy has so far relied on pharmacological, ionic or genetic manipulation of cells, ex-vivo brain tissue or intact animals, failing to recapitulate most of the epilepsies, which are triggered by unknown causes. Here, we report the spontaneous emergence of epileptiform patterns in spheroids of rodent primary hippocampal cells cultured in physiological condition, i.e., in the absence of a known initiating insult, detected by microelectrode array electrophysiology. Three distinct electrical phenotypes, i.e. interictal (between seizures), ictal (seizure) or mixed, arise from DIV10 to DIV35. In particular, the tonic-clonic ictal discharges become the most prominent at DIV28-35. These patterns exhibit electrographic and spectral features that strikingly resemble those observed in the hippocampus of in vitro and in vivo rodent epilepsy models, as well as of drug-resistant epileptic humans. Remarkably, not all spheroids exhibit full-blown ictal activity, bringing parallelism with the yet unanswered question of why a brain becomes epileptic and a seizure is generated. This evidence warrants caution against hippocampal cell-based therapies for regenerative purposes, as they may initiate epileptogenesis; at the same time, hippocampal spheroids lend themselves as reductionist model supporting high-throughput pre-clinical research on epileptic syndromes involving the hippocampus.

neuroscience↗