Prepubertal NMN Administration is associated with changes in hippocampal neurogenesis-related markers and amelioration of cognitive deficits

Schizophrenia (SCZ) is a neurodevelopmental disorder in which cognitive impairment constitutes a core determinant of long-term disability, yet existing treatments offer limited benefit. The prepubertal period represents a critical window for early intervention, as metabolic and neuroplastic abnormalities are potentially reversible. This study investigated whether prepubertal nicotinamide mononucleotide (NMN) administration is associated with the amelioration of cognitive deficits and changes in hippocampal neurogenesis-related markers in a two-hit (TH) mouse model of SCZ.

Male offspring exposed to maternal immune activation and subsequent chronic unpredictable stress received NMN (2 g/L in drinking water) from postnatal day (PND) 21 to PND 30. Behavioral testing (Morris water maze and novel object recognition), immunofluorescence, transmission electron microscopy, and biochemical assays were performed alongside in vitro neural stem cell (NSC) experiments under neuroinflammatory conditions. NMN intervention was associated with improved spatial learning in the MWM and enhanced exploratory/cognitive performance in the NOR test, accompanied by increased densities of radial glia-like cells (EdU⁺/SOX2⁺/GFAP⁺), proliferative progenitors (Ki67⁺/DCX⁺), and NeuN⁺ cells in the dentate gyrus.

These changes in neurogenesis-related markers were positively correlated with behavioral performance. Concurrently, hippocampal mitochondrial ultrastructure, ATP and NAD⁺ levels, mtDNA copy number, citrate synthase activity, and coenzyme Q10 levels showed patterns consistent with improved mitochondrial content and homeostasis. In vitro, NMN was associated with increased NSC viability, reduced apoptosis, and altered expression of neuronal versus glial lineage markers.

At the signaling level, NMN treatment was associated with increased SIRT1 expression and decreased p53 acetylation levels, accompanied by increased PI3K/AKT/mTOR phosphorylation levels; the SIRT1 inhibitor EX527 attenuated these protective effects in vitro. These findings provide experimental evidence that prepubertal NMN administration in the combined TH schizophrenia model is associated with concurrent improvements in neurogenesis-related markers, mitochondrial homeostasis indices, and cognitive-related behavioral performance, potentially involving the SIRT1–p53–PI3K/AKT/mTOR signaling pathway. However, whether changes in neurogenesis-related markers are causally required for cognitive improvement, and which component of the two-hit model NMN primarily acts upon, remain to be established in future studies.

We thank the Laboratory of Neural Injury and Repair, School of Basic Medical Sciences, Ningxia Medical University, for providing technical support in behavioral experiments and histological analysis. This work was supported by the National Natural Science Foundation of China (grant numbers 82560277 and 40012125). These authors contributed equally: Zhi-Lun Yang, Jun-Jie Li.

General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, China School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, Ningxia, China Zhi-Lun Yang, Jun-Jie Li, Zi-Qi Feng, Chen Guo, Yan-Bo Liu, Yu Shao, Hao-Wen Lv & Kang Wu The authors declare no competing interests. All animal experiments were approved by the Animal Ethics Committee of Ningxia Medical University (approval number: KYLL-2025-0838) and were performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH), USA. All the mice were humanely euthanized upon completion of the experiments.