Ntrk1, also known as Neurotrophic tyrosine kinase receptor 1, is the high-affinity receptor for Nerve Growth Factor, regulating neural development and differentiation. It is involved in multiple pathways, such as the AMPK/ULK1/FUNDC1 pathway related to mitophagy, and crosstalks with the Hippo tumour suppressor pathway through Yes-associated protein (YAP) [2,3]. Deregulation of Ntrk1 activity is associated with several human disorders, including congenital insensitivity to pain with anhidrosis (CIPA) and various cancers [3].

In a mouse Ntrk1-knockdown model, Ntrk1 knockdown induced cognitive impairment and hippocampal neuronal damage. This occurred through the suppression of mitophagy via inactivating the AMPK/ULK1/FUNDC1 pathway. Treatment with BAY-3827 exacerbated depressive-like behavior in these mice. In vitro, Ntrk1 knockdown attenuated neuronal viability, NeuN expression, ATP production, mitochondrial membrane potential, and mitophagy, while enhancing apoptosis and ROS production. Pre-treatment with O304 and rapamycin abrogated the suppression of mitophagy and the promotion of neuronal damage [1].

In conclusion, Ntrk1 is crucial for normal neural function, especially in maintaining hippocampal neuronal integrity and cognitive function. The Ntrk1-knockdown mouse model has provided valuable insights into the role of Ntrk1 in cognitive impairment due to hippocampal neuronal damage, potentially guiding the development of novel treatment strategies for such conditions [1].

References:

1. Yang, Kai, Wu, Jue, Li, Shang, Yuan, Jun-Liang, Yin, Cheng-Hong. 2023. NTRK1 knockdown induces mouse cognitive impairment and hippocampal neuronal damage through mitophagy suppression via inactivating the AMPK/ULK1/FUNDC1 pathway. In Cell death discovery, 9, 404. doi:10.1038/s41420-023-01685-7. https://pubmed.ncbi.nlm.nih.gov/37907480/

2. Yang, Xinyuan, Shen, He, Buckley, Brian, Han, Su-Xia, Zhang, Jianmin. 2018. NTRK1 is a positive regulator of YAP oncogenic function. In Oncogene, 38, 2778-2787. doi:10.1038/s41388-018-0609-1. https://pubmed.ncbi.nlm.nih.gov/30542115/

3. Pierotti, Marco A, Greco, Angela. 2005. Oncogenic rearrangements of the NTRK1/NGF receptor. In Cancer letters, 232, 90-8. doi:. https://pubmed.ncbi.nlm.nih.gov/16242838/