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

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 A Rivera de Jesús; 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

doi:10.1038/s41593-024-01782-5

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

Nat Neurosci. 2024 Dec;27(12):2487-2499. doi: 10.1038/s41593-024-01782-5. Epub 2024 Nov 15.

Authors

John P Andrews^#¹, Jinghui Geng^#^{2

3}, Kateryna Voitiuk^#^{3

4}, Matthew A T Elliott^{3

4}, David Shin¹, Ash Robbins^{2

3}, Alex Spaeth^{2

3}, Albert Wang¹, Lin Li⁵, Daniel Solis⁴, Matthew G Keefe¹, Jessica L Sevetson^{3

6}, Julio A Rivera de Jesús⁷, Kevin C Donohue⁸, H Hanh Larson⁹, Drew Ehrlich^{3

10}, Kurtis I Auguste¹, Sofie Salama^{3

6}, Vikaas Sohal⁸, Tal Sharf⁴, David Haussler^{2

3

4}, Cathryn R Cadwell^{1

9

11}, David V Schaffer^{5

7

12

13

14

15}, Edward F Chang^{16

17}, Mircea Teodorescu^{18

19

20}, Tomasz Jan Nowakowski^{21

22

23

24

25}

Affiliations

¹ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
² Department of Electrical and Computer Engineering, University of California, Santa Cruz, Santa Cruz, CA, USA.
³ UC Santa Cruz Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA, USA.
⁴ Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, USA.
⁵ California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA.
⁶ Department of Molecular, Cell & Developmental Biology, University of California, Santa Cruz, Santa Cruz, USA.
⁷ Department of Bioengineering, University of California, Berkeley, California, CA, USA.
⁸ Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA, USA.
⁹ Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
¹⁰ Department of Computational Media, University of California, Santa Cruz, Santa Cruz, CA, USA.
¹¹ Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
¹² Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, CA, USA.
¹³ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
¹⁴ Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, USA.
¹⁵ Innovative Genomics Institute (IGI), University of California, Berkeley, Berkeley, CA, USA.
¹⁶ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. [email protected].
¹⁷ Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA. [email protected].
¹⁸ Department of Electrical and Computer Engineering, University of California, Santa Cruz, Santa Cruz, CA, USA. [email protected].
¹⁹ UC Santa Cruz Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA, USA. [email protected].
²⁰ Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, USA. [email protected].
²¹ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. [email protected].
²² Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA, USA. [email protected].
²³ Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA. [email protected].
²⁴ Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA. [email protected].
²⁵ Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA. [email protected].

^# Contributed equally.

PMID: 39548326
DOI: 10.1038/s41593-024-01782-5

Abstract

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.

MeSH terms

Action Potentials / physiology
Adult
Dependovirus / genetics
Female
Genetic Vectors
Hippocampus* / physiology
Humans
Male
Middle Aged
Nerve Net / physiology
Neurons / physiology
Optogenetics* / methods

Abstract

MeSH terms

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