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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Vahid Rahmati - , Jena University Hospital (Author)
  • Jurgen Graf - , Jena University Hospital (Author)
  • Mihai Ceanga - , Jena University Hospital (Author)
  • Dario Cuevas Rivera - , Chair of cognitive computational neuroscience (Author)
  • Holger Haselmann - , Jena University Hospital (Author)
  • Sabine Liebscher - , Hospital of the Ludwig-Maximilians-University (LMU) Munich, Innsbruck Medical University (Author)
  • Harald Pruss - , Charité – Universitätsmedizin Berlin, German Center for Neurodegenerative Diseases (DZNE) - - Partner Site Berlin (Author)
  • Knut Holthoff - , Jena University Hospital (Author)
  • Knut Kirmse - , University of Würzburg (Author)
  • Christian Geis - , Jena University Hospital (Author)

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.

Details

Original languageEnglish
Pages (from-to)4550–4562
Number of pages13
JournalMolecular psychiatry
Volume31
Early online date31 Mar 2026
Publication statusE-pub ahead of print - 31 Mar 2026
Peer-reviewedYes

External IDs

PubMed 41917496
Scopus 105034750063

Keywords

Keywords

  • Long-term depression, Synaptic plasticity, Receptor encephalitis, Cerebrospinal-fluid, Pyramidal cells, Mouse model, Network, Ripple, Memory, Autoantibodies