Journal Article

DZNE-2026-00217

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Elevated calneuron-1, an accessory subunit of muscarinic receptors, induces frontotemporal dysconnectivity and schizophrenia-like deficits.

Oelschlegel, A. M. ; Pöpplau, J. A. ; Ryzynski, A. ; Hradsky, J. ; Reddy, P. P. ; Navarro, G. ; Reyes-Resina, I. ; Yuanxiang, P. ; Sosulina, L.DZNE* ; Kaneko, H. ; Sahu, G. ; Günther, A. ; Andres-Alonso, M. ; Lopez-Rojas, J. ; Aly, A. A. A. ; Bauer, P. ; Mikulovic, S. ; Xia, Z. ; Mikhaylova, M. ; Remy, S.DZNE* ; Hanganu-Opatz, I. ; Karpova, A. ; Kreutz, M. R. (Last author)DZNE*

2026
Cell Press [Cambridge, Mass.]

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Please use a persistent id in citations: doi:10.1016/j.neuron.2025.10.038

Abstract: Calneuron-1 is a Ca2+ sensor that has been linked in several genome-wide association studies to schizophrenia (SCZ). We show that calneuron-1 expression is elevated in the dorsolateral prefrontal cortex of SCZ patients and that overexpression in the medial prefrontal cortex (mPFC) of mice elicits SCZ-related behavioral disabilities, disrupts rhythmogenesis within the mPFC, impairs functional connectivity between the hippocampus and the mPFC, and causes deficits in muscarinic synaptic plasticity. These neurophysiological signatures of SCZ are linked to the role of calneuron-1 as an accessory subunit of muscarinic M1 receptors (M1Rs). Calneuron-1 displaces Gαq11 from the third intracellular loop of M1R at elevated [Ca2+]i, thereby disrupting downstream signaling. The M1R agonist xanomeline, shown to reduce positive and negative symptoms of SCZ and recently approved for clinical use, impedes this calneuron-1/M1R interaction, which leads to restoration of G-protein coupling, muscarinic synaptic plasticity, and network communication. Collectively, our data indicate a potential causative pathomechanism of SCZ.

Keyword(s): Animals (MeSH) ; Mice (MeSH) ; Humans (MeSH) ; Schizophrenia: metabolism (MeSH) ; Schizophrenia: genetics (MeSH) ; Schizophrenia: physiopathology (MeSH) ; Receptor, Muscarinic M1: metabolism (MeSH) ; Receptor, Muscarinic M1: agonists (MeSH) ; Prefrontal Cortex: metabolism (MeSH) ; Male (MeSH) ; Neuronal Plasticity: physiology (MeSH) ; Neuronal Plasticity: drug effects (MeSH) ; Female (MeSH) ; Hippocampus: metabolism (MeSH) ; Hippocampus: physiopathology (MeSH) ; Mice, Inbred C57BL (MeSH) ; Thiadiazoles: pharmacology (MeSH) ; Pyridines (MeSH) ; Calneuron-1 ; medial prefrontal cortex ; muscarinic M1 receptors ; schizophrenia ; xanomeline ; Receptor, Muscarinic M1 ; xanomeline ; Thiadiazoles ; Pyridines

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Contributing Institute(s):

1. Clinical Neurophysiology and Memory (AG Düzel)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 15 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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