Psychomotor disturbances in neuronal growth regulator-1-deficient (Negr1−/−) mice are associated with alterations in hippocampal and skeletal muscle signaling

The motor domain has emerged as a fundamental transdiagnostic dimension of neuropsychiatric disorders, reflecting dysfunction in neural circuits underlying movement, cognition, and behavior. Neuronal growth regulator 1 (NEGR1) is a synaptic cell adhesion molecule genetically linked to multiple neuropsychiatric disorders. Despite its function in neural development and widespread expression in the central and peripheral nervous systems, its involvement in the motor domain remains unknown.

Here, we investigated the motor domain by comprehensively characterizing psychomotor function and associated molecular alterations in adult male and female Negr1−/− mice. Negr1 deficiency produced a motor phenotype characterized by altered run characteristics, gait dynamics, including swing speed, stride length and muscle strength, with molecular changes in the hippocampus and skeletal muscle. Male Negr1−/− mice exhibited increased casein kinase 2 (CK2) activity in the hippocampus and skeletal muscle, whereas females showed reduced activity of CK2 and Rho-associated coiled-coil-containing protein kinase (ROCK) only in the hippocampus.

Skeletal muscle further exhibited transcript-level alterations in genes encoding proteins involved in mitochondrial biology and contractility. Together, these findings indicate co-occurring central and peripheral molecular alterations underlying the multisystem psychomotor phenotype associated with Negr1 deficiency. We sincerely thank Professor Michael K.E.

Schaefer (Professor of Experimental Anesthesiology, University Medical Center of the Johannes Gutenberg University (JGU) Mainz, Germany) for kindly providing the Negr1 KO mouse line used in this study. This research was funded by the Estonian Research Council, project numbers PRG 685 and PRG2544. The research was conducted using the research infrastructure “National Center for Translational and Clinical Research”, funded by the Estonian Research Council (TARISTU24-TK22).

Institute of Biomedicine and Translational Medicine, Department of Physiology, University of Tartu, 19 Ravila Street, Tartu, 50411, Estonia Srirathi Muthuraman, Mohan Jayaram, Birgit Pilve, Arpana Reinsberg, Kaie Mikheim, Eero Vasar, Mari-Anne Philips & Katyayani Singh Institute of Chemistry, University of Tartu, Ravila 14A, Tartu, 50411, Estonia The authors declare no competing of interest. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Below is the link to the electronic supplementary material.

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