PXD032055

PXD032055 is an original dataset announced via ProteomeXchange.

Title	Human NMDAR autoantibodies disrupt excitatory-inhibitory balance leading to hippocampal network hypersynchrony
Description	Specific autoantibodies against the NMDA-receptor (NMDAR) GluN1 subunit cause severe and debilitating NMDAR-encephalitis. Autoantibodies induce prototypic disease symptoms resembling schizophrenia, including psychosis and cognitive dysfunction. Using a mouse passive transfer model applying human monoclonal anti-GluN1-autoantibodies, we observed CA1 pyramidal neuron hypoexcitability, reduced AMPA-receptor (AMPAR) signaling, and faster synaptic inhibition resulting in disrupted excitatory-inhibitory balance. Functional alterations were supported by widespread remodeling of the hippocampal proteome, including changes in glutamatergic and GABAergic neurotransmission. At the network level, anti-GluN1-autoantibodies amplified gamma oscillations and disrupted theta-gamma coupling. A data-informed network model revealed that lower AMPAR strength and faster GABAA-receptor current kinetics chiefly account for these abnormal oscillations. As predicted by our model and evidenced experimentally, positive allosteric modulation of AMPARs alleviated aberrant gamma activity and thus reinforced the causative effects of the excitatory-inhibitory imbalance. Collectively, NMDAR-hypofunction-induced aberrant synaptic, cellular, and network dynamics provide new mechanistic insights into disease symptoms in NMDAR-encephalitis and schizophrenia.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:03:51.127.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Emilio Cirri
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-03-03 13:01:49	ID requested
1	2023-09-24 16:34:20	announced
2	2023-11-14 07:56:32	announced	2023-11-14: Updated project metadata.
⏵ 3	2024-10-22 06:03:51	announced	2024-10-22: Updated project metadata.

10.1016/J.CELREP.2023.113166;

submitter keyword: network oscillation, excitatory-inhibitory imbalance, autoantibodies, NMDA receptor encephalitis,NMDA receptor, theta-gamma coupling, neural network modeling

Christian Geis
contact affiliation	Department for Neurology Section Translational Neuroimmunology Jena University Hospital Am Klinikum 1, D-07747 Jena, Germany
contact email	Christian.Geis@med.uni-jena.de
lab head
Emilio Cirri
contact affiliation	Leibniz Institute on Ageing Fritz Lipmann Institute Jena
contact email	emilio.cirri@fli-leibniz.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/09/PXD032055

PRIDE project URI

• PRIDE
  1. PXD032055
     1. Label: PRIDE project
     2. Name: Human NMDAR autoantibodies disrupt excitatory-inhibitory balance leading to hippocampal network hypersynchrony