Multimodal evaluation of network activity and optogenetic interventions in human hippocampal slices

This paper demonstrated for the first time that optogenetic tools can be used to modulate network activity in human brain slices, bridging the long-lasting gap between human and animal studies. The MaxOne Single-Well High-Density Microelectrode (HD-MEA) System was used to record the spontaneous and light-evoked activity of human hippocampal slices.

Andrews, J.P., Geng, J., Voitiuk, K. et al. Multimodal evaluation of network activity and optogenetic interventions in human hippocampal slices. Nat Neurosci (2024). https://doi.org/10.1038/s41593-024-01782-5

Epilepsy is a disease of aberrant neuronal activity that results from an imbalance of excitation and inhibition, with recurrent seizures as a common denominator. Optogenetic interventions have yielded promising results in animal models of epilepsy, however their application to human neural circuits has been limited thus far.

In this study, the authors described an experimental platform where epileptiform activity was assessed in primary human organotypic hippocampal slices and rehabilitated by the cell-type specific, adeno-associated virus-mediated optogenetic inhibition of a glutamatergic subpopulation. This work combined high spatio-temporal recordings of MaxWell Biosystems’ MaxOne Single-Well HD-MEA System and the authors’ custom light delivery system for precise optogenetic control.

Spontaneous activity of hippocampal neurons (labelled by NeuN in black) from human hippocampal slices transduced with an inhibitory Channelrhodopsin captured on the MaxOne Single-Well HD-MEA system from MaxWell Biosystems. Activity in the dentate gyrus (dg) depicted as a heatmap and electrical footprints of single neurons with high spatiotemporal resolution (top panel). Once the slice illuminated, the neuronal activity is rapidly silenced, which is reversed when the light is switched off (bottom panel).

“The high resolution was a significant factor that allowed us to see seizure propagation and shutdown at a cellular level within the human slice tissue”, says co-first author Kateryna Voitiuk. “The MEA combined many scales of measurement that unlocked a lot of key insights: we were able to analyze single-cell waveforms, network-level dynamics between neurons, and local field potential propagation at the same time. Combining all of these electrophysiology modalities with tissue histology was really breathtaking”.

This work highlights the use of human brain tissue for evaluating different techniques to modulate network activity “with the long-term goal of de-risking potential therapeutic interventions”. Combined with capabilities to modulate and record neuronal network activity, human brain tissue serves as an accessible model for studying human brain functional dynamics.

Citation

John P. Andrews, Jinghui Geng, Kateryna Voitiuk, Matthew A. T. Elliott, David Shin, Ash Robbins, Alex Spaeth, Albert Wang, Lin Li, Daniel Solis, Matthew G. Keefe, Jessica L. Sevetson, Julio Rivera-de Jesus, Kevin C. Donohue, H. Hanh Larson, Drew Ehrlich, Kurtis I. Auguste, Sofie Salama, Vikaas Sohal, Tal Sharf, David Haussler, Cathryn R. Cadwell, David V. Schaffer, Edward F. Chang, Mircea Teodorescu, Tomasz Jan Nowakowski. Nat Neurosci (2024). https://doi.org/10.1038/s41593-024-01782-5

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