RESUMO
This study aimed to investigate the mechanism of the effect of TREM2 on cognitive function in autistic mice. TREM2 overexpression and knockdown viruses were given to autism spectrum disorder (ASD) mice and BV2 microglia cell line. To assess cognitive performance, all groups of mice took part in the open field, new object recognition, Morris water maze, and three-box social experiments. Double immunofluorescence labeling demonstrated co-localization of LC3II and NeuN. Proteins from the PI3K/Akt/mTOR pathway were identified. In vivo, behavior studies revealed that TREM2 could successfully improve ASD mice's social interaction and cognitive performance. Besides, we discovered that TREM2 could increase autophagy in ASD mice. In vitro, overexpressing TREM2 reduced the expression of PI3K/AKT/mTOR pathway proteins, whereas knocking down TREM2 increased the expression of PI3K/AKT/mTOR pathway proteins. In conclusion, TREM2 could inhibit PI3K/Akt/mTOR signaling pathway, enhance autophagy, and improve the social communication ability and cognitive function of ASD mice.
Assuntos
Autofagia , Cognição , Glicoproteínas de Membrana , Microglia , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Receptores Imunológicos , Transdução de Sinais , Serina-Treonina Quinases TOR , Animais , Cognição/fisiologia , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Fosfatidilinositol 3-Quinases/metabolismo , Receptores Imunológicos/metabolismo , Receptores Imunológicos/genética , Serina-Treonina Quinases TOR/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos , Microglia/metabolismo , Masculino , Transtorno Autístico/metabolismo , Transtorno Autístico/genética , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/psicologia , Modelos Animais de Doenças , Comportamento Animal , Linhagem Celular , Camundongos Endogâmicos C57BL , Comportamento SocialRESUMO
BACKGROUND: Autism spectrum disorder (ASD) encompasses a diverse range of neurodevelopmental disorders, but the precise underlying pathogenesis remains elusive. This study aim to explore the potential mechanism of TREM2 in regulating microglia function in ASD. MATERIALS AND METHODS: The offspring rat model of ASD was established through prenatal exposure to valproic acid (VPA), and the behavioral symptoms of the ASD model were observed. On postnatal day (PND) 7 and PND 28, the effects of prenatally exposure to VPA on synaptic development and microglia phenotype of offspring rats were observed. Primary microglia were cultured in vitro. Lentivirus and adenovirus were utilized to interfere with TREM2 and overexpress TREM2. RESULTS: Prenatally VPA exposure induced offspring rats to show typical ASD core symptoms, which led to abnormal expression of synapse-related proteins in the prefrontal cortex of offspring rats, changed the phenotype of microglia in offspring rats, promoted the polarization of microglia to pro-inflammatory type, and increased inflammatory response. The experimental results in vitro showed that overexpression of TREM2 could increase the expression of Gephyrin, decrease the content of CD86 protein and increase the content of CD206 protein. In addition, after the expression of TREM2 was interfered, the content of p-P38 MAPK protein increased and the content of p-ELK-1 protein decreased. CONCLUSION: The protective influence of TREM2 on the VPA-induced ASD model is attributed to its inhibition of the P38 MAPK pathway, this protective effect may be achieved by promoting the polarization of microglia to anti-inflammatory phenotype and improving the neuronal synaptic development.
