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

• Published in: Nature neuroscience 2024-12, Vol.27 (12), p.2487-2499
• Main Authors: Andrews, John P., Geng, Jinghui, Voitiuk, Kateryna, Elliott, Matthew A. T., Shin, David, Robbins, Ash, Spaeth, Alex, Wang, Albert, Li, Lin, Solis, Daniel, Keefe, Matthew G., Sevetson, Jessica L., Rivera de Jesús, Julio A., Donohue, Kevin C., Larson, H. Hanh, Ehrlich, Drew, Auguste, Kurtis I., Salama, Sofie, Sohal, Vikaas, Sharf, Tal, Haussler, David, Cadwell, Cathryn R., Schaffer, David V., Chang, Edward F., Teodorescu, Mircea, Nowakowski, Tomasz Jan
• Format: Article
• Language: English
• Subjects: 13/106; 13/109; 38/35; 42/44; 631/378/1689/178; 631/378/340; 9/74; Action Potentials - physiology; Adult; Animal Genetics and Genomics; Arrays; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Brain; Brain slice preparation; Dependovirus - genetics; Disease control; Epilepsy; Female; Genetic Vectors; Genetics; High density; Hippocampus; Hippocampus - physiology; Humans; Hyperactivity; Information processing; Male; Microelectrodes; Middle Aged; Nerve Net - physiology; Neurobiology; Neurons; Neurons - physiology; Neurophysiology; Neurosciences; Optics; Optogenetics - methods; Seizures; Tissues; Tropism
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/s41593-024-01782-5

Seizures are made up of the coordinated activity of networks of neurons, suggesting that control of neurons in the pathologic circuits of epilepsy could allow for control of the disease. Optogenetics has been effective at stopping seizure-like activity in non-human disease models by increasing inhibitory tone or decreasing excitation, although this effect has not been shown in human brain tissue. Many of the genetic means for achieving channelrhodopsin expression in non-human models are not possible in humans, and vector-mediated methods are susceptible to species-specific tropism that may affect translational potential. Here we demonstrate adeno-associated virus–mediated, optogenetic reductions in network firing rates of human hippocampal slices recorded on high-density microelectrode arrays under several hyperactivity-provoking conditions. This platform can serve to bridge the gap between human and animal studies by exploring genetic interventions on network activity in human brain tissue. Brain slices offer an experimental window into human neurophysiology. Using high-density microelectrode array recordings and adeno-associated virus–mediated optogenetics, the authors demonstrate that optogenetic targeting of CAMK2A+ neurons can affect network activity in human hippocampal slices.