TY  - JOUR
AU  - Oelschlegel, Anja M
AU  - Pöpplau, Jastyn A
AU  - Ryzynski, Alexandre
AU  - Hradsky, Johannes
AU  - Reddy, Pasham Parameshwar
AU  - Navarro, Gemma
AU  - Reyes-Resina, Irene
AU  - Yuanxiang, PingAn
AU  - Sosulina, Liudmila
AU  - Kaneko, Hiroshi
AU  - Sahu, Giriraj
AU  - Günther, Anne
AU  - Andres-Alonso, Maria
AU  - Lopez-Rojas, Jeffrey
AU  - Aly, Ahmed A A
AU  - Bauer, Pavol
AU  - Mikulovic, Sanja
AU  - Xia, Zifeng
AU  - Mikhaylova, Marina
AU  - Remy, Stefan
AU  - Hanganu-Opatz, Ileana
AU  - Karpova, Anna
AU  - Kreutz, Michael R
TI  - Elevated calneuron-1, an accessory subunit of muscarinic receptors, induces frontotemporal dysconnectivity and schizophrenia-like deficits.
JO  - Neuron
VL  - 114
IS  - 4
SN  - 0896-6273
CY  - [Cambridge, Mass.]
PB  - Cell Press
M1  - DZNE-2026-00217
SP  - 679 - 698.e11
PY  - 2026
AB  - 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.
KW  - Animals
KW  - Mice
KW  - Humans
KW  - Schizophrenia: metabolism
KW  - Schizophrenia: genetics
KW  - Schizophrenia: physiopathology
KW  - Receptor, Muscarinic M1: metabolism
KW  - Receptor, Muscarinic M1: agonists
KW  - Prefrontal Cortex: metabolism
KW  - Male
KW  - Neuronal Plasticity: physiology
KW  - Neuronal Plasticity: drug effects
KW  - Female
KW  - Hippocampus: metabolism
KW  - Hippocampus: physiopathology
KW  - Mice, Inbred C57BL
KW  - Thiadiazoles: pharmacology
KW  - Pyridines
KW  - Calneuron-1 (Other)
KW  - medial prefrontal cortex (Other)
KW  - muscarinic M1 receptors (Other)
KW  - schizophrenia (Other)
KW  - xanomeline (Other)
KW  - Receptor, Muscarinic M1 (NLM Chemicals)
KW  - xanomeline (NLM Chemicals)
KW  - Thiadiazoles (NLM Chemicals)
KW  - Pyridines (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41412129
DO  - DOI:10.1016/j.neuron.2025.10.038
UR  - https://pub.dzne.de/record/285351
ER  -