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

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. edward.chang@ucsf.edu.
¹⁷ Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA. edward.chang@ucsf.edu.
¹⁸ Department of Electrical and Computer Engineering, University of California, Santa Cruz, Santa Cruz, CA, USA. mteodore@ucsc.edu.
¹⁹ UC Santa Cruz Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA, USA. mteodore@ucsc.edu.
²⁰ Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, USA. mteodore@ucsc.edu.
²¹ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. tomasz.nowakowski@ucsf.edu.
²² Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA, USA. tomasz.nowakowski@ucsf.edu.
²³ Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA. tomasz.nowakowski@ucsf.edu.
²⁴ Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA. tomasz.nowakowski@ucsf.edu.
²⁵ Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA. tomasz.nowakowski@ucsf.edu.

^# Contributed equally.

PMID: 39548326
PMCID: PMC11881784 (available on 2025-12-01)
DOI: 10.1038/s41593-024-01782-5

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

John P Andrews et al. Nat Neurosci. 2024 Dec.

. 2024 Dec;27(12):2487-2499.

doi: 10.1038/s41593-024-01782-5. Epub 2024 Nov 15.

Authors

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. edward.chang@ucsf.edu.
¹⁷ Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA. edward.chang@ucsf.edu.
¹⁸ Department of Electrical and Computer Engineering, University of California, Santa Cruz, Santa Cruz, CA, USA. mteodore@ucsc.edu.
¹⁹ UC Santa Cruz Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA, USA. mteodore@ucsc.edu.
²⁰ Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, USA. mteodore@ucsc.edu.
²¹ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. tomasz.nowakowski@ucsf.edu.
²² Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA, USA. tomasz.nowakowski@ucsf.edu.
²³ Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA. tomasz.nowakowski@ucsf.edu.
²⁴ Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA. tomasz.nowakowski@ucsf.edu.
²⁵ Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA. tomasz.nowakowski@ucsf.edu.

^# Contributed equally.

PMID: 39548326
PMCID: PMC11881784 (available on 2025-12-01)
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.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

Comment in

Channeling Seizure Control: Optogenetics in Human Brain Slices.
Rolston JD. Rolston JD. Epilepsy Curr. 2025 Apr 13;25(4):275-276. doi: 10.1177/15357597251333157. eCollection 2025 Jul-Aug. Epilepsy Curr. 2025. PMID: 40235936 Free PMC article. No abstract available.

References

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Comment in

References

Methods-only references

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous