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Stereotactic/ Functional Rapid Fire Abstract

Stereotactic and Functional

Optogenetic modulation of epileptiform activity in human hippocampus

Saturday, May 4, 2024
3:45 PM – 3:47 PM CT
Location:  S405b
Disclosure(s):
John P. Andrews, MD: No financial relationships to disclose
Edward Chang, MD: Echo Neurotechnologies: Ownership Interest (Ongoing)
Introduction: Epilepsy is a disease of neuronal activity. If we can control neurons that fire pathologically, we can modify the disease. Using optogenetics, neuronal activity can be controlled in non-human model systems using light-activated ion channels. Data on optogenetics in human brain tissue is extremely limited. There is currently no framework for evaluating the efficacy of optogenetic tools on disease models in human brain tissue. Here, we test whether optogenetic tools be delivered to ex vivo human hippocampus and be used to modulate seizure-like activity.

Methods: Hippocampi resected for refractory epilepsy are collected the day of surgery, sliced to 300um and plated on cell inserts at the air-fluid interface in cell-culture media. Slices are transduced day of surgery with an adenoviral vector driving expression of HCKCR1, a recently described potassium specific, inactivating channelrhodopsin. After incubation, slices are plated on high-density microelectrode arrays (HD-MEAs) for electrophysiologic recordings. Direct application of bicuculline was used to model seizure-like activity.

Results: Robust recordings of human hippocampal slices were achieved, with up to 80 units recorded simultaneously (median 38). Slices expressed HCKCR1 at day 4-6. Illumination of slices with 530nm light led to cessation of population firing during spontaneous activity (p=6.67e-51) and during bicuculline modelled seizure-like activity (p=1.84e-56). A closed-loop illumination system was successful at repetitive activity inhibition.

Conclusion : In this proof-of-concept model, we use high-density multi-unit recordings of human hippocampus to demonstrate the first report of optogenetic inhibition of epileptiform activity in human hippocampal tissue. The platform described allows for investigation of optogenetic efficacy in human neuronal circuits.