New strong and reliable human neuron connections discovered

© 2023 EPFL

© 2023 EPFL

The brain is made up of billions of neurons that communicate with each other by forming trillions of synapses. Transmission between these synapses is the primary method of communication between neurons and has been extensively studied in rodents. However, far less is known about synaptic transmission in the human brain. An exciting new study in a front cover paper published in Cerebral Cortex, set out to quantitatively characterize a selected neural pathway in the human neocortex.

The study has broken new ground by finding excitatory synaptic connections in layer 2/3 of human middle temporal gyrus (involved in cognitive processes) are much stronger and more reliable compared to mouse. It was known that human neurons receive about 3-times more synapses, but this new study now shows that the number of synapses between pairs of connected neurons is comparable between rodents and humans. This means that human neurons receive information from many more neurons and communication between these many pairs is thus more reliable in human neurons, compared to mouse. This highlights the vital importance of further studying the fundamental properties of human local circuits not only to bridge the gap in cross-scale understanding of the human brain in health, but also widen the panorama on successful human-specific treatments in disease patients.

Prof. Felix Schürmann, Computing Director, EPFL Blue Brain Project, explains, “Gaining a comprehensive understanding of the building blocks (i.e. neurons) of the human brain, their wiring rules, connection properties, and how information is processed and transmitted in human microcircuits are crucial.” Recognizing this, this study combines the expertise of the EPFL Blue Brain Project who are digitally reconstructing and simulating the mouse brain with researchers from the Vrije Universiteit, The Hebrew University of Jerusalem (HUJI), Laboratorio Cajal de Circuitos Corticales, Madrid, Amsterdam Universitair Medische Centra, and the Allen Institute for Brain Science. Using multiple whole-cell recordings of clusters of up to four neurons, the group characterized transmission via synapses between pyramidal neurons in layers 2/3 using neurosurgically resected human middle temporal gyrus. They found that local connectivity between pairs of neurons is comparable with mouse layer 2/3 connections, but the synaptic connections in human are three times stronger and more reliable.

“We also revealed that synaptic transmission between pairs of neurons in human (but not mouse) triggers NMDA receptor activation,” reveals, Senior Lead Author, Prof. Christiaan P.J. de Kock, Vrije Universiteit, Amsterdam. (NMDA receptors play a crucial role in regulating a wide variety of neurophysiological functions, including neuronal plasticity, excitability, learning and memory formation).

This was unexpected - that local electrical properties would be sufficient to trigger NMDA receptor activation, as activation of these channels are typically associated with robust depolarization and action potential spiking. This NMDA receptor activation prolongs excitation within neurons, potentially leading to persistent network activity which could hint that this persistent activity leads to thedevelopment or maintenance of cognitive connections, which is key to how microcircuits function.

Christiaan continues, “The new computational modeling approach developed by Prof. Idan Segev and his team from the HUJI, was absolutely key in uncovering the (local) properties of strong synapses in human. The simulations showed that, mainly due to their specific morphology, local voltage changes in human neurons in response to the activation of just one presynaptic cell, are much higher compared to those changes in mouse neurons. This voltage change is sufficient to activate NMDA receptors in human (but not mouse) connections. The modeling results pointed us in the right direction after which we designed the experiment in which we were able to validate the predictions from the model - specifically, selectively blocking the NMDA receptor in human synapses to prove their contribution”.

Inviting further investigation into the microcircuit functions in humans

“We know that cortical microcircuit consists of multiple layers and numerous cell-types and our new study highlights important microcircuit properties from which language processing in human brain may emerge,” discloses Prof. Idan Segev. “Most importantly, our finding that local electrical properties in human pyramidal neurons are sufficient to activate NMDA receptors has direct implications for how we should think about information transfer, synaptic plasticity and learning, and persistent network activity in the human brain. We now need to investigate whether our findings are generalizable for additional connections within the human microcircuit. It will also be essential to understand how NMDA receptor activation could support microcircuit function in human. Our study is a great step forward, including the key mission of simulating (and understanding) of the dynamics of large parts of human neuronal circuits. This is only the beginning – a very exciting beginning!”

Knowledge and skills sharing for open science

“This study is a beautiful example of interdisciplinary research applied to one of the big remaining mysteries in neuroscience - the human brain,” comments Prof. Henry Markram, Founder and Director of the Blue Brain Project. “The painstakingly precise work needed to characterize human tissue is complicated by its scarce availability, requiring tremendous commitment from the next generation scientists such as Sarah Hunt, Yoni Leibner and Blue Brain’s Natali Barros-Zulaica and Lida Kanari. The modeling effort by Natali showed that human synapses are more efficient compared to mice, thus uncovering part of why human synapses are more reliable. Furthermore, the computational analysis from Lida was key in determining the morphological cell-types that were part of the connections investigated. This is a unique but critical achievement when studying the human brain in view of the many cell-types present. Finally, such a collaboration and the sharing of skills and resources is fundamental to contributing to open science and the progress it brings, as demonstrated here,” he concludes.

About the Authors

The scientists involved in this study include:

Sarah Hunt, Eline J. Mertens, Tim S. Heistek, Mahesh M. Karnani, Romy Aardse, René Wilbers, Djai B. Heyer, Natalia A. Goriounova, Matthijs B. Verhoog, Guilherme Testa-Silva, Joshua Obermayer, Tamara Versluis, Huibert D. Mansvelder, Christiaan P.J. de Kock - Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, the Netherlands

Yoni Leibner, Idan Segev - Department of Neurobiology and Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Israel

Natali Barros-Zulaica, Lida Kanari, Henry Markram, Felix Schürmann - Blue Brain Project, Ecole polytechnique fédérale de Lausanne, Campus Biotech, Geneva 1202, Switzerland

Ruth Benavides-Piccione, Javier DeFelipe - Laboratorio Cajal de Circuitos Corticales - Universidad Politécnica de Madrid and Instituto Cajal, Spain

Philip de Witt-Hamer, Sander Idema, David P. Noske, Johannes C. Baayen - Neurosurgery Department, Amsterdam Universitair Medische Centra, the Netherlands

Ed S. Lein - Allen Institute for Brain Science, Seattle, USA

For more information, please contact Blue Brain’s Communications Manager – [email protected]


This study was supported by funding to the Blue Brain Project, a research center of the Ecole Polytechnique fédérale de Lausanne (EPFL), by support from the Swiss government’s ETH Board of the Swiss Federal Institutes of Technology, by The Spanish “Ministerio de Cienciae Innovación” (grant PGC2018-094307-B-I00) and by the Center for Neurogenomics and Cognitive Research

(VU Amsterdam). HDM received funding for this work from the US Brain Initiative by the National Institutes of Health under Award Number U01MH114812, the European Union’s Horizon 2020 Framework Programme for Research and Innovation under the Specific Grant Agreement No. 945539 (Human Brain Project SGA3), and NWO Gravitation program BRAINSCAPES: A Roadmap

from Neurogenetics to Neurobiology (NWO: 024.004.012). IS received generous support from the Drahi family foundation, from the European Union’s Horizon Frame-work Program for Research and Innovation under the Specific Grant Agreement No. 785907 (Human Brain Project SGA2), the ETH domain for the Blue Brain Project, the Gatsby Charitable Foundation, and the NIH Grant

Agreement U01MH114812.


Hunt, S., Leibner, Y., Mertens, E. J., Barros-Zulaica, N., Kanari, L., Heistek, T. S., Karnani, M. M., Aardse, R., Wilbers, R., Heyer, D. B., Goriounova, N. A., Verhoog, M. B., Testa-Silva, G., Obermayer, J., Versluis, T., Benavides-Piccione, R., de Witt-Hamer, P., Idema, S., Noske, D. P., D. P., Baayen, J. C., Lein, E. S., DeFelipe, J., Markram, H., Mansvelder, H. D., Schürmann, F., Segev, I., & de Kock, C. P. J. (2022). Strong and reliable synaptic communication between pyramidal neurons in adult human cerebral cortex. Cerebral Cortex, bhac246.