Chrm1-KO Mouse

CHRM1, encoding the muscarinic acetylcholine receptor M1, is a key component in cholinergic neurotransmission. It is involved in multiple pathways, such as the cAMP/PKA/CREB pathway, and plays a significant role in various biological processes including neuronal function, sleep regulation, and cell proliferation. Genetic models, like gene knockout (KO) mouse models, have been crucial for studying its functions [2,3,4,5,6].

In KO mouse models, genetic ablation of CHRM1 in astrocytes led to defects in neural stem cell survival, neuronal differentiation, maturation, and integration in the dentate gyrus, impairing adult hippocampal neurogenesis (AHN) and contextual fear memory. These impairments were rescued by overexpression of astrocytic CHRM1, revealing a critical role for astrocytes in mediating cholinergic regulation of AHN and memory through CHRM1 [1]. In melanoma, high-throughput pharmacologic and genetic in vivo CRISPR screens showed that endogenous DOPA inhibits melanoma through suppression of CHRM1 signaling, suggesting CHRM1 as a new therapeutic target [3]. In pancreatic ductal adenocarcinoma (PDAC), subdiaphragmatic vagotomy or Chrm1 knockout accelerated tumorigenesis, while enhanced cholinergic signaling through CHRM1 suppressed PDAC cell growth, indicating CHRM1 as a potentially attractive therapeutic target [5].

In conclusion, CHRM1 is essential for normal neuronal function, especially in the context of AHN and memory. Model-based research, particularly KO/CKO mouse models, has revealed its significance in diseases like Alzheimer's disease, Parkinson's disease, frontotemporal dementia, melanoma, and PDAC. Understanding CHRM1's functions provides potential therapeutic strategies for these diseases [1,3,4,5].

References:

1. Li, Wei-Peng, Su, Xiao-Hong, Hu, Neng-Yuan, Yang, Jian-Ming, Gao, Tian-Ming. 2022. Astrocytes Mediate Cholinergic Regulation of Adult Hippocampal Neurogenesis and Memory Through M1 Muscarinic Receptor. In Biological psychiatry, 92, 984-998. doi:10.1016/j.biopsych.2022.04.019. https://pubmed.ncbi.nlm.nih.gov/35787318/

2. Zhu, Gemin, Fang, Yuan, Cui, Xiaoli, Kang, Xiaogang, Zhao, Rui. 2021. Magnolol upregulates CHRM1 to attenuate Amyloid-β-triggered neuronal injury through regulating the cAMP/PKA/CREB pathway. In Journal of natural medicines, 76, 188-199. doi:10.1007/s11418-021-01574-2. https://pubmed.ncbi.nlm.nih.gov/34705126/

3. Doepner, Miriam, Lee, Inyoung, Natale, Christopher A, Feigin, Michael E, Ridky, Todd W. 2022. Endogenous DOPA inhibits melanoma through suppression of CHRM1 signaling. In Science advances, 8, eabn4007. doi:10.1126/sciadv.abn4007. https://pubmed.ncbi.nlm.nih.gov/36054350/

4. Sabbir, Mohammad Golam, Speth, Robert C, Albensi, Benedict C. . Loss of Cholinergic Receptor Muscarinic 1 (CHRM1) Protein in the Hippocampus and Temporal Cortex of a Subset of Individuals with Alzheimer's Disease, Parkinson's Disease, or Frontotemporal Dementia: Implications for Patient Survival. In Journal of Alzheimer's disease : JAD, 90, 727-747. doi:10.3233/JAD-220766. https://pubmed.ncbi.nlm.nih.gov/36155524/

5. Renz, Bernhard W, Tanaka, Takayuki, Sunagawa, Masaki, Olive, Kenneth P, Wang, Timothy C. 2018. Cholinergic Signaling via Muscarinic Receptors Directly and Indirectly Suppresses Pancreatic Tumorigenesis and Cancer Stemness. In Cancer discovery, 8, 1458-1473. doi:10.1158/2159-8290.CD-18-0046. https://pubmed.ncbi.nlm.nih.gov/30185628/

6. Niwa, Yasutaka, Kanda, Genki N, Yamada, Rikuhiro G, Sumiyama, Kenta, Ueda, Hiroki R. . Muscarinic Acetylcholine Receptors Chrm1 and Chrm3 Are Essential for REM Sleep. In Cell reports, 24, 2231-2247.e7. doi:10.1016/j.celrep.2018.07.082. https://pubmed.ncbi.nlm.nih.gov/30157420/