2. Academic Validation
  3. Impaired olfactory bulb neurogenesis mediated by Notch1 contributes to olfactory dysfunction in mice chronically exposed to methamphetamine

Impaired olfactory bulb neurogenesis mediated by Notch1 contributes to olfactory dysfunction in mice chronically exposed to methamphetamine

  • Cell Biol Toxicol. 2025 Feb 20;41(1):46. doi: 10.1007/s10565-025-10004-y.
Cihang Gu # 1,  Zhuo Wang # 2,  Wenyu Luo 1,  Haosen Ling 1,  Xilie Cui 1,  Tongtong Deng 3,  Kuan Li 1,  Wei Huang 1,  Qiqian Xie 1,  Bowen Tao 1,  Xiaolan Qi 4,  Xiaojia Peng 1,  Jiuyang Ding 5,  Pingming Qiu 6 7
Affiliations

Affiliations

  • 1 Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou, 510515, China.
  • 2 Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou, 510006, China.
  • 3 School of Medicine, South China University of Technology, Guangzhou, 510006, China.
  • 4 Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, Guizhou Medical University, Guiyang, 550004, China.
  • 5 Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, Guizhou Medical University, Guiyang, 550004, China. djy09099@163.com.
  • 6 Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou, 510515, China. qiupmfy@126.com.
  • 7 Department of Thyroid Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China. qiupmfy@126.com.
  • # Contributed equally.
PMID: 39976779 DOI: 10.1007/s10565-025-10004-y
Abstract

Methamphetamine (Meth) is a potent central nervous system stimulant with high addictive potential and neurotoxic effects. Chronic use results in significant damage in various brain functions, including cognition, memory, and sensory perception. Olfactory dysfunction is a notable yet often overlooked consequence of Meth abuse, and its underlying mechanisms are not fully understood. This study investigates the mechanisms of Meth-induced olfactory impairment through a thorough examination of olfactory bulb (OB) neurogenesis. We found that chronic Meth abuse impaired olfactory function in mice by not only reducing the self-renewal of subventricular zone (SVZ) neural stem cells (NSCs) but also altering their differentiation potential, leading their differentiation into astrocytes at the expense of neurons. Mechanistically, Meth inhibits autophagosome-lysosome fusion by downregulating Syntaxin 17 (Stx17), which reduces autophagic flux. In NSCs, Autophagy tightly regulates Notch1 levels, and impaired autophagic degradation of Notch1 leads to its abnormal activation. This alters NSCs fate determination, ultimately affecting OB neurogenesis. Our study reveals that Meth impairs olfactory function through autophagic dysfunction and aberrant Notch1 signaling. Understanding these mechanisms not only provides new insights into Meth-induced olfactory dysfunction but also offers potential targets for developing therapies to alleviate Meth-induced neurotoxicity and sensory damage in the future.

Keywords

Methamphetamine; Neurogenesis; Notch1 signaling; Olfactory bulb; Olfactory dysfunction.

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