ω-3PUFAs Improve Cognitive Impairments Through Ser133 Phosphorylation of CREB Upregulating BDNF/TrkB Signal in Schizophrenia

• Published in: Neurotherapeutics 2020-07, Vol.17 (3), p.1271-1286
• Main Authors: Guo, Cuiping, Liu, Yi, Fang, Mao-sheng, Li, Yuanyuan, Li, Wensheng, Mahaman, Yacoubou Abdoul Razak, Zeng, Kuan, Xia, Yiyuan, Ke, Dan, Liu, Rong, Wang, Jian-Zhi, Shen, Hui, Shu, Xiji, Wang, Xiaochuan
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - metabolism; Cells, Cultured; Cognitive ability; Cognitive Dysfunction - chemically induced; Cognitive Dysfunction - drug therapy; Cognitive Dysfunction - metabolism; Cyclic AMP response element-binding protein; Cyclic AMP Response Element-Binding Protein - metabolism; Dizocilpine Maleate - toxicity; Excitatory Amino Acid Antagonists - toxicity; Fatty Acids, Omega-3 - pharmacology; Fatty Acids, Omega-3 - therapeutic use; Hippocampus; Male; Mental disorders; Mutation; Neurobiology; Neurology; Neurosciences; Neurosurgery; Organ Culture Techniques; Original; Original Article; Phosphorylation; Phosphorylation - drug effects; Phosphorylation - physiology; Polyunsaturated fatty acids; Rats; Rats, Sprague-Dawley; Receptor, trkB - metabolism; Schizophrenia; Schizophrenia - chemically induced; Schizophrenia - drug therapy; Schizophrenia - metabolism; Serine - metabolism; Signal transduction; Signal Transduction - drug effects; Signal Transduction - physiology; Supplements; TrkB receptors
• ISSN: 1933-7213; 1878-7479; 1878-7479
• DOI: 10.1007/s13311-020-00859-w

Schizophrenia (SZ) is a serious mental condition and is associated with cognitive impairments. Brain-derived neurotrophic factor (BDNF) is one of the learning- and memory-related molecules found in the CNS and its level was reported to be reduced in SZ brain, while ω-3 polyunsaturated fatty acids (ω-3PUFAs) could improve SZ symptoms, but its mechanism of action remains unknown. Using MK801 injection–induced SZ rat model, we here found that supplementation with ω-3PUFAs improved the levels of p-CREB, BDNF, and p-TrkB in the brain of SZ rats, and restore hippocampal neuronal damage, thereby reducing cognitive impairments in SZ rats. However, overexpression of AAV9/CREB S133A (CREB inactivated mutation) downregulated BDNF/TrkB signaling pathway and remarkably abolished the preventive effect of ω-3PUFAs in MK801-induced schizophrenia. Interestingly, AAV9/CREB S133D (CREB activated mutation) improved synaptic dysfunctions and cognitive defects in MK801 rats. In conclusion, these findings indicate that MK801-induced SZ lesions dephosphorylate CREB at Ser133 site, leading to neuron damage, and ω-3PUFAs improve SZ cognitive impairments by upregulating the CREB/BDNF/TrkB pathway, which provides new clues for the mechanism of SZ cognitive impairments, and a basis for therapeutic intervention.