---
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abstract:
- lang: eng
text: Hippocampal CA3 pyramidal neurons (PNs) form the largest autoassociative network
in the mammalian brain. Whether CA3–CA3 recurrent connectivity is genetically
preconfigured or environmentally shaped during ongoing memory storage is currently
unknown. To address this question, we performed multicellular patch-clamp-based
circuit mapping of up to eight CA3 PNs in the mouse hippocampus at multiple postnatal
time points (P7–8, P18–25, and P45–50). Here, we show that the hippocampal CA3
network undergoes a developmental transformation from local, dense, and random
connectivity to a distributed, sparse, and structured configuration. Thus, sparse
and structured connectivity may emerge via experience-dependent mechanisms. In
parallel, the strength of single synapses is downregulated; single synaptic events
are sufficient to trigger postsynaptic spiking early in development, whereas spatial
summation of several inputs is required at later time points. Biologically inspired
models of memory storage by Hebbian synaptic plasticity and retrieval via pattern
completion suggest that developmental changes improve specific aspects of memory
storage and retrieval. Our results imply a developmental transformation of the
neuronal code and the memory functions in the hippocampal CA3 network.
acknowledged_ssus:
- _id: PreCl
- _id: Bio
- _id: M-Shop
- _id: ScienComp
acknowledgement: 'We thank Jose Guzman, Simon Hippenmeyer, and Tim Vogels for critically
reading the manuscript, Jozsef Csicsvari for useful discussions, Florian Marr for
technical assistance, and Eleftheria Kralli-Beller for manuscript editing. This
research was supported by the Scientific Services Units (SSUs) of ISTA: the preclinical
facility (PCF) provided housing and breeding of the animals, the imaging and optics
facility (IOF) offered technical training and state of the art equipment, the Miba
machine shop contributed to the construction and maintenance of multicellular recording
setups, and the scientific computing unit helped with the large-scale simulations.
The project received funding from the European Union’s Horizon 2020 research and
innovation programme (ERC Advanced Grants No 692692 GIANTSYN and 101199096 CA3-SYNGRAM
to P.J.; Marie Skłodowska-Curie Grant 754411 to V.V.B.; Marie Skłodowska-Curie Grant
101026635 to J.F.W.), the Fond zur Förderung der Wissenschaftlichen Forschung (P
36232-B, PAT4178023, and 10.55776/CoE16 to P.J.), and the Nomis Foundation (fellowship
to A.N.-O.). V.V.B. received funding from a CONACyT fellowship (289638).'
article_number: '5540'
article_processing_charge: Yes
article_type: original
author:
- first_name: Victor M
full_name: Vargas Barroso, Victor M
id: 2F55A9DE-F248-11E8-B48F-1D18A9856A87
last_name: Vargas Barroso
- first_name: Jake
full_name: Watson, Jake
id: 63836096-4690-11EA-BD4E-32803DDC885E
last_name: Watson
orcid: 0000-0002-8698-3823
- first_name: Andrea C
full_name: Navas Olivé, Andrea C
id: 739d26c9-52e8-11ee-8d72-f14d3893b4ce
last_name: Navas Olivé
orcid: 0000-0002-9280-8597
- first_name: Alois
full_name: Schlögl, Alois
id: 45BF87EE-F248-11E8-B48F-1D18A9856A87
last_name: Schlögl
orcid: 0000-0002-5621-8100
- first_name: Peter M
full_name: Jonas, Peter M
id: 353C1B58-F248-11E8-B48F-1D18A9856A87
last_name: Jonas
orcid: 0000-0001-5001-4804
citation:
ama: Vargas Barroso VM, Watson J, Navas Olivé AC, Schlögl A, Jonas PM. Developmental
emergence of sparse and structured synaptic connectivity in the hippocampal CA3
memory circuit. Nature Communications. 2026;17. doi:10.1038/s41467-026-71914-x
apa: Vargas Barroso, V. M., Watson, J., Navas Olivé, A. C., Schlögl, A., & Jonas,
P. M. (2026). Developmental emergence of sparse and structured synaptic connectivity
in the hippocampal CA3 memory circuit. Nature Communications. Springer
Nature. https://doi.org/10.1038/s41467-026-71914-x
chicago: Vargas Barroso, Victor M, Jake Watson, Andrea C Navas Olivé, Alois Schlögl,
and Peter M Jonas. “Developmental Emergence of Sparse and Structured Synaptic
Connectivity in the Hippocampal CA3 Memory Circuit.” Nature Communications.
Springer Nature, 2026. https://doi.org/10.1038/s41467-026-71914-x.
ieee: V. M. Vargas Barroso, J. Watson, A. C. Navas Olivé, A. Schlögl, and P. M.
Jonas, “Developmental emergence of sparse and structured synaptic connectivity
in the hippocampal CA3 memory circuit,” Nature Communications, vol. 17.
Springer Nature, 2026.
ista: Vargas Barroso VM, Watson J, Navas Olivé AC, Schlögl A, Jonas PM. 2026. Developmental
emergence of sparse and structured synaptic connectivity in the hippocampal CA3
memory circuit. Nature Communications. 17, 5540.
mla: Vargas Barroso, Victor M., et al. “Developmental Emergence of Sparse and Structured
Synaptic Connectivity in the Hippocampal CA3 Memory Circuit.” Nature Communications,
vol. 17, 5540, Springer Nature, 2026, doi:10.1038/s41467-026-71914-x.
short: V.M. Vargas Barroso, J. Watson, A.C. Navas Olivé, A. Schlögl, P.M. Jonas,
Nature Communications 17 (2026).
corr_author: '1'
das_tickbox: '1'
dataavailabilitystatement: Source data are provided with this paper. Additional original
data are available from the corresponding author upon request. Code is available
from https://doi.org/10.15479/AT-ISTA-21442 under the link https://research-explorer.ista.ac.at/download/21442/21443/ca3simu-vargas2026v1.tar.gz
date_created: 2026-06-30T13:05:52Z
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date_updated: 2026-07-01T06:47:49Z
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doi: 10.1038/s41467-026-71914-x
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name: Synaptic networks of human brain
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name: Reglas de Conectividad funcional en el hipocampo
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publisher: Springer Nature
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title: Developmental emergence of sparse and structured synaptic connectivity in the
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ama: Schlögl A. CA3Simu v1.06 (vargas2026v1). 2026. doi:10.15479/AT-ISTA-21442
apa: Schlögl, A. (2026). CA3Simu v1.06 (vargas2026v1). Institute of Science and
Technology Austria. https://doi.org/10.15479/AT-ISTA-21442
chicago: Schlögl, Alois. “CA3Simu v1.06 (Vargas2026v1).” Institute of Science and
Technology Austria, 2026. https://doi.org/10.15479/AT-ISTA-21442.
ieee: A. Schlögl, “CA3Simu v1.06 (vargas2026v1).” Institute of Science and Technology
Austria, 2026.
ista: Schlögl A. 2026. CA3Simu v1.06 (vargas2026v1), Institute of Science and Technology
Austria, 10.15479/AT-ISTA-21442.
mla: Schlögl, Alois. CA3Simu v1.06 (Vargas2026v1). Institute of Science and
Technology Austria, 2026, doi:10.15479/AT-ISTA-21442.
short: A. Schlögl, (2026).
corr_author: '1'
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keyword:
- hypocampus
- ca3 simulations
- modelling
license: https://opensource.org/licenses/GPL-3.0
month: '03'
oa: 1
project:
- _id: e62b56fe-ab3c-11f0-94c7-d181dd352b3b
grant_number: '101199096'
name: Synaptic mechanisms of engram storage and retrieval in CA3 hippocampal microcircuits
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grant_number: P36232
name: Mechanisms of GABA release in hippocampal circuits
- _id: 8d9195e9-16d5-11f0-9cad-d075be887a1e
grant_number: PAT 4178023
name: Synaptic networks of human brain
- _id: 25B7EB9E-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '692692'
name: Biophysics and circuit function of a giant cortical glutamatergic synapse
publisher: Institute of Science and Technology Austria
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acknowledged_ssus:
- _id: M-Shop
- _id: PreCl
- _id: Bio
acknowledgement: "This project was supported by the following funding agencies: ERC
under the European\r\nUnion's Horizon 2020 research and innovation program (ERC
Advanced Grants No 692692\r\n“GIANTSYN” and 101199096 “CA3-SYNGRAM” to P.J.), the
Fonds zur Förderung der\r\nwissenschaftlichen Forschung (P 36232-B, stand-alone
grant, PAT 4178023, principal\r\ninvestigator project, and 10.55776/CoE 16 “GABA
neurons” to P.J.), and the European Union’s\r\nHorizon 2020 research and innovation
programme under the Marie Skłodowska-Curie grant\r\nagreement (No 101034413, to
K.L.)."
alternative_title:
- ISTA Thesis
article_processing_charge: No
author:
- first_name: Peipeng
full_name: Lin, Peipeng
id: 7E3060D0-A92C-11E9-A326-26C8E5697425
last_name: Lin
citation:
ama: 'Lin P. Calibrating the teacher synapse: Mechanisms and functional significance
of presynaptic inhibition at hippocampal mossy fiber synapses. 2026. doi:10.15479/AT-ISTA-22735'
apa: 'Lin, P. (2026). Calibrating the teacher synapse: Mechanisms and functional
significance of presynaptic inhibition at hippocampal mossy fiber synapses.
Institute of Science and Technology Austria. https://doi.org/10.15479/AT-ISTA-22735'
chicago: 'Lin, Peipeng. “Calibrating the Teacher Synapse: Mechanisms and Functional
Significance of Presynaptic Inhibition at Hippocampal Mossy Fiber Synapses.” Institute
of Science and Technology Austria, 2026. https://doi.org/10.15479/AT-ISTA-22735.'
ieee: 'P. Lin, “Calibrating the teacher synapse: Mechanisms and functional significance
of presynaptic inhibition at hippocampal mossy fiber synapses,” Institute of Science
and Technology Austria, 2026.'
ista: 'Lin P. 2026. Calibrating the teacher synapse: Mechanisms and functional significance
of presynaptic inhibition at hippocampal mossy fiber synapses. Institute of Science
and Technology Austria.'
mla: 'Lin, Peipeng. Calibrating the Teacher Synapse: Mechanisms and Functional
Significance of Presynaptic Inhibition at Hippocampal Mossy Fiber Synapses.
Institute of Science and Technology Austria, 2026, doi:10.15479/AT-ISTA-22735.'
short: 'P. Lin, Calibrating the Teacher Synapse: Mechanisms and Functional Significance
of Presynaptic Inhibition at Hippocampal Mossy Fiber Synapses, Institute of Science
and Technology Austria, 2026.'
corr_author: '1'
das_tickbox: '0'
date_created: 2026-08-18T15:23:41Z
date_published: 2026-08-25T00:00:00Z
date_updated: 2026-08-31T11:11:55Z
day: '25'
ddc:
- '571'
- '573'
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department:
- _id: GradSch
- _id: PeJo
doi: 10.15479/AT-ISTA-22735
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language:
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license: https://creativecommons.org/licenses/by-nc-nd/4.0/
month: '08'
oa_version: Published Version
page: '88'
project:
- _id: 25B7EB9E-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '692692'
name: Biophysics and circuit function of a giant cortical glutamatergic synapse
- _id: e62b56fe-ab3c-11f0-94c7-d181dd352b3b
grant_number: '101199096'
name: Synaptic mechanisms of engram storage and retrieval in CA3 hippocampal microcircuits
- _id: bd88be38-d553-11ed-ba76-81d5a70a6ef5
grant_number: P36232
name: Mechanisms of GABA release in hippocampal circuits
- _id: 8d9195e9-16d5-11f0-9cad-d075be887a1e
grant_number: PAT 4178023
name: Synaptic networks of human brain
- _id: fc2ed2f7-9c52-11eb-aca3-c01059dda49c
call_identifier: H2020
grant_number: '101034413'
name: 'IST-BRIDGE: International postdoctoral program'
publication_identifier:
isbn:
- 978-3-99078-088-6
issn:
- 2663-337X
publication_status: published
publisher: Institute of Science and Technology Austria
researchdata_availability: upon request
status: public
supervisor:
- first_name: Peter M
full_name: Jonas, Peter M
id: 353C1B58-F248-11E8-B48F-1D18A9856A87
last_name: Jonas
orcid: 0000-0001-5001-4804
supplementarymaterial: yes
title: 'Calibrating the teacher synapse: Mechanisms and functional significance of
presynaptic inhibition at hippocampal mossy fiber synapses'
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type: dissertation
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...
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abstract:
- lang: eng
text: 'Our brain has remarkable computational power, generating sophisticated behaviors,
storing memories over an individual’s lifetime, and producing higher cognitive
functions. However, little of our neuroscience knowledge covers the human brain.
Is this organ truly unique, or is it a scaled version of the extensively studied
rodent brain? Combining multicellular patch-clamp recording with expansion-based
superresolution microscopy and full-scale modeling, we determined the cellular
and microcircuit properties of the human hippocampal CA3 region, a fundamental
circuit for memory storage. In contrast to neocortical networks, human hippocampal
CA3 displayed sparse connectivity, providing a circuit architecture that maximizes
associational power. Human synapses showed unique reliability, high precision,
and long integration times, exhibiting both species- and circuit-specific properties.
Together with expanded neuronal numbers, these circuit characteristics greatly
enhanced the memory storage capacity of CA3. Our results reveal distinct microcircuit
properties of the human hippocampus and begin to unravel the inner workings of
our most complex organ. '
acknowledged_ssus:
- _id: Bio
- _id: PreCl
- _id: LifeSc
- _id: M-Shop
- _id: ScienComp
acknowledgement: We thank Florian Marr for excellent technical assistance, Christina
Altmutter and Julia Flor for technical support, Alois Schlögl for programming, Todor
Asenov for development of the transportation box for human brain tissue, Tim Vogels
for guidance on simulations, Marcus Huber for mathematical advice, Walter Kaufmann
for assistance with handling frozen tissue, and Eleftheria Kralli-Beller for manuscript
editing. This research was supported by the Scientific Services Units (SSUs) of
ISTA, and we are grateful for assistance from Christoph Sommer and the Imaging and
Optics Facility, Preclinical Facility, Lab Support Facility, Miba Machine Shop,
and Scientific Computing. We are particularly grateful to the patient donors for
their support of this project and also acknowledge the excellent support of the
Medical University of Vienna Department of Neurosurgery staff; Romana Hoeftberger
and the Division of Neuropathology and Neurochemistry; Gregor Kasprian and the Division
of Neuroradiology and Musculoskeletal Radiology; and Christoph Baumgartner, Martha
Feucht, and Ekaterina Pataraia for their clinical care of the patients included
in this study. We thank Laura Jonkman, the NABCA biobank, and postmortem brain sample
donors for their support of this research. The project received funding from the
European Research Council (ERC) under the European Union’s Horizon 2020 research
and innovation programme (advanced grant no. 692692 to P.J. and Marie Skłodowska-Curie
Actions Individual Fellowship no. 101026635 to J.F.W.), the Austrian Science Fund
(FWF; grant PAT 4178023 to P.J. and grant DK W1232 to M.R.T. and J.G.D.), the Austrian
Academy of Sciences (DOC fellowship 26137 to M.R.T.), and a NOMIS-ISTA fellowship
(to A.N.-O.).
article_processing_charge: Yes (via OA deal)
article_type: original
author:
- first_name: Jake
full_name: Watson, Jake
id: 63836096-4690-11EA-BD4E-32803DDC885E
last_name: Watson
orcid: 0000-0002-8698-3823
- first_name: Victor M
full_name: Vargas Barroso, Victor M
id: 2F55A9DE-F248-11E8-B48F-1D18A9856A87
last_name: Vargas Barroso
- first_name: Rebecca
full_name: Morse, Rebecca
id: ceb89ae7-dc8d-11ea-abe3-da3301d0eab4
last_name: Morse
- first_name: Andrea C
full_name: Navas Olivé, Andrea C
id: 739d26c9-52e8-11ee-8d72-f14d3893b4ce
last_name: Navas Olivé
orcid: 0000-0002-9280-8597
- first_name: Mojtaba
full_name: Tavakoli, Mojtaba
id: 3A0A06F4-F248-11E8-B48F-1D18A9856A87
last_name: Tavakoli
orcid: 0000-0002-7667-6854
- first_name: Johann G
full_name: Danzl, Johann G
id: 42EFD3B6-F248-11E8-B48F-1D18A9856A87
last_name: Danzl
orcid: 0000-0001-8559-3973
- first_name: Matthias
full_name: Tomschik, Matthias
last_name: Tomschik
- first_name: Karl
full_name: Rössler, Karl
last_name: Rössler
- first_name: Peter M
full_name: Jonas, Peter M
id: 353C1B58-F248-11E8-B48F-1D18A9856A87
last_name: Jonas
orcid: 0000-0001-5001-4804
citation:
ama: Watson J, Vargas Barroso VM, Morse R, et al. Human hippocampal CA3 uses specific
functional connectivity rules for efficient associative memory. Cell. 2025;188(2):501-514.e18.
doi:10.1016/j.cell.2024.11.022
apa: Watson, J., Vargas Barroso, V. M., Morse, R., Navas Olivé, A. C., Tavakoli,
M., Danzl, J. G., … Jonas, P. M. (2025). Human hippocampal CA3 uses specific functional
connectivity rules for efficient associative memory. Cell. Elsevier. https://doi.org/10.1016/j.cell.2024.11.022
chicago: Watson, Jake, Victor M Vargas Barroso, Rebecca Morse, Andrea C Navas Olivé,
Mojtaba Tavakoli, Johann G Danzl, Matthias Tomschik, Karl Rössler, and Peter M
Jonas. “Human Hippocampal CA3 Uses Specific Functional Connectivity Rules for
Efficient Associative Memory.” Cell. Elsevier, 2025. https://doi.org/10.1016/j.cell.2024.11.022.
ieee: J. Watson et al., “Human hippocampal CA3 uses specific functional connectivity
rules for efficient associative memory,” Cell, vol. 188, no. 2. Elsevier,
p. 501–514.e18, 2025.
ista: Watson J, Vargas Barroso VM, Morse R, Navas Olivé AC, Tavakoli M, Danzl JG,
Tomschik M, Rössler K, Jonas PM. 2025. Human hippocampal CA3 uses specific functional
connectivity rules for efficient associative memory. Cell. 188(2), 501–514.e18.
mla: Watson, Jake, et al. “Human Hippocampal CA3 Uses Specific Functional Connectivity
Rules for Efficient Associative Memory.” Cell, vol. 188, no. 2, Elsevier,
2025, p. 501–514.e18, doi:10.1016/j.cell.2024.11.022.
short: J. Watson, V.M. Vargas Barroso, R. Morse, A.C. Navas Olivé, M. Tavakoli,
J.G. Danzl, M. Tomschik, K. Rössler, P.M. Jonas, Cell 188 (2025) 501–514.e18.
corr_author: '1'
date_created: 2025-01-26T23:01:49Z
date_published: 2025-01-23T00:00:00Z
date_updated: 2026-04-14T08:34:32Z
day: '23'
ddc:
- '570'
department:
- _id: JoDa
- _id: PeJo
- _id: GradSch
doi: 10.1016/j.cell.2024.11.022
ec_funded: 1
external_id:
isi:
- '001408395600001'
pmid:
- '39667938'
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