Elevated calneuron-1, an accessory subunit of muscarinic receptors, induces frontotemporal dysconnectivity and schizophrenia-like deficits
Calneuron-1 is a Ca<sup>2+</sup> 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 Gαq<sub>11</sub> from the third intracellular loop of M1R at elevated [Ca<sup>2+</sup>]<sub>i</sub>, 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.
Authors
- Gemma Navarro (ORCID: https://orcid.org/0000-0003-4654-0873)
- Jeffrey Lopez‐Rojas (ORCID: https://orcid.org/0000-0001-9648-4051)
- Johannes Hradsky
- Anne Günther
- Alexandre Ryzynski
- Ahmed A. A. Aly (ORCID: https://orcid.org/0000-0001-8843-5807)
- Hiroshi Kaneko (ORCID: https://orcid.org/0000-0002-3782-8122)
- Anja M. Oelschlegel (ORCID: https://orcid.org/0009-0008-0675-1469)
- Anna Karpova (ORCID: https://orcid.org/0000-0001-7423-4764)
- Liudmila Sosulina
- Pasham Parameshwar Reddy
- Pavol Bauer (ORCID: https://orcid.org/0000-0002-1171-9972)
- Jastyn A. Pöpplau (ORCID: https://orcid.org/0000-0002-4350-3164)
- Giriraj Sahu (ORCID: https://orcid.org/0000-0001-6566-9563)
- Stefan Remy (ORCID: https://orcid.org/0000-0002-3386-1662)
- Zifeng Xia
- Irene Reyes‐Resina (ORCID: https://orcid.org/0000-0003-2077-2537)
- Maria Andres‐Alonso (ORCID: https://orcid.org/0000-0002-1585-539X)
- Ileana L. Hanganu‐Opatz (ORCID: https://orcid.org/0000-0002-4787-1765)
- Marina Mikhaylova (ORCID: https://orcid.org/0000-0001-7646-1346)
- Sanja Mikulovic (ORCID: https://orcid.org/0000-0001-6115-6007)
- PingAn Yuanxiang (ORCID: https://orcid.org/0000-0002-3746-3282)
- Michael R. Kreutz (ORCID: https://orcid.org/0000-0003-0575-6950)
Institutions
- Universität Hamburg (DE)
- German Center for Neurodegenerative Diseases (DE)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- University Medical Center Hamburg-Eppendorf (DE)
- Centro de Investigación Biomédica en Red (ES)
- Center for Behavioral Brain Sciences (DE)
- Leibniz Institute for Neurobiology (DE)
Publication Details
- Journal
- Neuron
- Published
- 2025-12-17
- DOI
- https://doi.org/10.1016/j.neuron.2025.10.038
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00