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  • Perspective
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Understanding neural circuit function through synaptic engineering

Nature Reviews Neuroscience volume 25, pages 131–139 (2024)Cite this article

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Abstract

Synapses are a key component of neural circuits, facilitating rapid and specific signalling between neurons. Synaptic engineering — the synthetic insertion of new synaptic connections into in vivo neural circuits — is an emerging approach for neural circuit interrogation. This approach is especially powerful for establishing causality in neural circuit structure–function relationships, for emulating synaptic plasticity and for exploring novel patterns of circuit connectivity. Contrary to other approaches for neural circuit manipulation, synaptic engineering targets specific connections between neurons and functions autonomously with no user-controlled external activation. Synaptic engineering has been successfully implemented in several systems and in different forms, including electrical synapses constructed from ectopically expressed connexin gap junction proteins, synthetic optical synapses composed of presynaptic photon-emitting luciferase coupled with postsynaptic light-gated channels, and artificial neuropeptide signalling pathways. This Perspective describes these different methods and how they have been applied, and examines how the field may advance.

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Fig. 1: Distinct features of synaptic engineering.
Fig. 2: Connexin-based engineered electrical synapses.
Fig. 3: Luciferase–channelrhodopsin-based engineered optical synapses.
Fig. 4: Engineered neuropeptide signalling.

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Acknowledgements

I.R. received financial support from the Israel Science Foundation (grant 1465/20). Research in the D.A.C.-R. laboratory was supported by grants from NIH (R01NS076558), the National Science Foundation (NSF IOS 1353845) and DP1NS111778 and by an HHMI Scholar Award. M.K. acknowledges financial support from the ERC (MechanoSystems, 715243), HFSP (CDA00023/2018), MCIN/ AEI/10.13039/501100011033/ FEDER ‘A way to make Europe’, PID2021-123812OB-I00, ‘Severo Ochoa’ program for Centres of Excellence in R&D (CEX2019-000910-S), Fundació Privada Cellex, Fundació Mir-Puig and Generalitat de Catalunya through the CERCA and Research program.

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Authors and Affiliations

  1. Department of Medical Neurobiology, Institute for Medical Research Israel−Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel

    Ithai Rabinowitch

  2. Wu Tsai Institute, Department of Neuroscience and Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA

    Daniel A. Colón-Ramos

  3. ICFO - Institut de Ciencies Fotoniques, The Barcelona Institute of Science and Technology, Castelldefels, Spain

    Michael Krieg

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Rabinowitch, I., Colón-Ramos, D.A. & Krieg, M. Understanding neural circuit function through synaptic engineering. Nat. Rev. Neurosci. 25, 131–139 (2024). https://doi.org/10.1038/s41583-023-00777-8

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