Anti-NMDAR encephalitis impairs intrinsic hippocampal dynamics through neuronal hypercoupling, hub dominance, and aberrant ensembles.

Overview

1. Section Translational Neuroimmunology, Department of Neurology, Jena University Hospital, 07747 Jena, Germany
2. Department of Neurology, Jena University Hospital, 07747 Jena, Germany
3. Department of Psychology, Technical University Dresden, 01187 Dresden, Germany
4. Institute of Clinical Neuroimmunology, Klinikum der Universität München, Ludwig-Maximilians University Munich, Martinsried, Germany
5. Institute of Systems Neuroscience, Medical University of Innsbruck, 6020 Innsbruck, Austria
6. Department of Neurology and Experimental Neurology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Berlin, 10117 Berlin, Germany
7. German Center for Neurodegenerative Diseases (DZNE) Berlin, 10117 Berlin, Germany
8. Department of Neurophysiology, Institute of Physiology, University of Würzburg, D-97070 Würzburg, Germany

Abstract

Autoimmune anti-NMDA-receptor encephalitis is characterized by autoantibody-induced NMDA receptor hypofunction leading to severe neuropsychiatric symptoms including psychosis, hallucinations, memory dysfunction and seizures. However, it remains enigmatic what changes in intrinsic network organization at the multi-neuronal level, serving as the neural substrate of brain function, underlie disease symptomology. Using a mouse model with passive-transfer of patient’s monoclonal anti-GluN1-autoantibodies, we performed two-photon in vivo recordings of spontaneous dynamics under light anesthesia in CA1 microcircuits, a key hippocampal area for memory processing. We find pronounced functional coupling and clustering between putative neurons (PNs), alongside an altered network architecture with pathological emergence of irregular neuronal ensembles. These alterations not only induce excessive hub-like properties but also contribute to the increased network’s intrinsic synchrony, despite its reduced baseline activity; this hypersynchrony was further supported by pathologically faster intra-ripple oscillations and amplified population bursts during these coincident events in vivo. Next, using electrophysiological data ex vivo, we show that this profound functional rewiring is associated with a selective preservation of effectively strong excitatory synapses, despite overall reduced excitation and augmented long-term depression. Furthermore, we find abnormal PN firing characteristics, higher transmission fidelity, and increased similarity of spontaneous spatiotemporal activity patterns, all reflecting dysregulated intrinsic organization of CA1 dynamics. Collectively, the aberrant reorganization of hippocampal microcircuits and altered intrinsic network activity patterns provide new mechanistic insights into the consequences of NMDAR hypofunction and pathomechanisms of anti-NMDAR encephalitis.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper says that its authors' code is available on request: it was not published with the paper, so there is nothing to verify.

Code availability

This paper does not report original code central to the main results. MATLAB toolboxes for the Brain Connectivity Toolbox (brain-connectivity-toolbox.net), NoRMCorre (https://github.com/porteralab/NoRMCorre), gini function (https://www.mathworks.com/matlabcentral/fileexchange/28080-gini-coefficient-and-the-lorentz-curve), UFARSA (https://github.com/VahidRahmati/UFARSA), FluoroSNNAP (https://www.seas.upenn.edu/~molneuro/software.html), FRACI (https://github.com/CABSEL/FARCI), as well as the MESc (https://femtonics.eu/ (https://femtonics.eu/products/#nav-software)) and Fiji (https://fiji.sc/) software programs are publicly available online.

Reproduced under the paper's license (CC BY), from the paper cited above.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none (its code is available on request), so it has no map.

Data

No dataset and no data link were found in the paper.

Data availability

Statistical data associated with this study are presented in Supplementary Table 1. Any additional information required to reanalyze the data reported in this work paper is available from the corresponding authors upon request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 2 keywords, 14 MeSH terms, 2 funders, 119 references.

Cite

This paper

Rahmati, V., Graf, J., Ceanga, M., Cuevas Rivera, D., Haselmann, H., Liebscher, S., Prüss, H., Holthoff, K., Kirmse, K., & Geis, C. (2026). Anti-NMDAR encephalitis impairs intrinsic hippocampal dynamics through neuronal hypercoupling, hub dominance, and aberrant ensembles. Molecular psychiatry, 31(8), 4550-4562. https://doi.org/10.1038/s41380-026-03568-6

Similar papers

The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.

[1] doi:10.7554/elife.82756 [code]

Network instability dynamics drive a transient bursting period in the developing hippocampus in vivo.

Journal: eLife

In common: mouse, 10 references, 5 authors

[2] doi:10.1038/s44319-024-00056-2

Converging synaptic and network dysfunctions in distinct autoimmune encephalitis.

Journal: EMBO reports

In common: other condition, cellular / molecular, 9 references, author Harald Prüss

[3] doi:10.1016/j.isci.2024.110997 [code]

Chemogenetic silencing reveals presynaptic G_i/o protein-mediated inhibition of developing hippocampal synchrony <i>in vivo</i>.

Journal: iScience

In common: mouse, 4 references, 2 authors

[4] doi:10.1038/s41467-024-47459-2 [code]

A primary sensory cortical interareal feedforward inhibitory circuit for tacto-visual integration.

Journal: Nature communications

In common: mouse, 1 reference, 3 authors

[5] doi:10.1126/sciadv.aec2042 [code]

IgLON5 autoimmune antibodies activate Tau via neuronal hyperactivity.

Journal: Science advances

In common: other condition, mouse, cellular / molecular, 7 references, author Harald Prüss

[6] doi:10.1038/s41467-024-44983-z [code]

A developmental increase of inhibition promotes the emergence of hippocampal ripples.

Journal: Nature communications

In common: mouse, 9 references

[7] doi:10.1371/journal.pbio.3002837 [code]

Functional networks of inhibitory neurons orchestrate synchrony in the hippocampus.

Journal: PLoS biology

In common: mouse, 9 references

[8] doi:10.1126/sciadv.abq7806

Microglia mediate neurocognitive deficits by eliminating C1q-tagged synapses in sepsis-associated encephalopathy.

Journal: Science advances

In common: other condition, mouse, cellular / molecular, 2 authors

[9] doi:10.3389/fnmol.2022.940005

Regulation of NMDA Receptor Signaling at Single Synapses by Human Anti-NMDA Receptor Antibodies.

Journal: Frontiers in molecular neuroscience

In common: other condition, cellular / molecular, 6 references

[10] doi:10.1162/netn.a.572 [code]

Functional connectivity is linked to symbolic BOLD patterns: Replication, extension, and clinical application of the human "Complexome".

Journal: Network neuroscience (Cambridge, Mass.)

In common: other condition, 3 references, author Harald Prüss

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion: code errors and mismatches between the code and the paper about this paper and its code, from readers and its authors, beside the paper and its tracing map.

Reproductions: reports from readers who ran the authors' code and did not get the paper's result, what they ran, with which environment, commit and data.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.