Autism risk gene KMT5B deficiency in prefrontal cortex induces synaptic dysfunction and social deficits via alterations of DNA repair and gene transcription
| العنوان: | Autism risk gene KMT5B deficiency in prefrontal cortex induces synaptic dysfunction and social deficits via alterations of DNA repair and gene transcription |
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| المؤلفون: | Ben Rein, Ping Zhong, Freddy Zhang, Kaijie Ma, Fengwei Yang, Zi-Jun Wang, Qing Cao, Jamal B Williams, Zhen Yan |
| المصدر: | Neuropsychopharmacology |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | DNA Repair, Transcription, Genetic, DNA repair, Prefrontal Cortex, Biology, Neurotransmission, Protein degradation, Article, Mice, 03 medical and health sciences, Glutamatergic, 0302 clinical medicine, Downregulation and upregulation, medicine, Animals, Autistic Disorder, Prefrontal cortex, Pharmacology, Glutamate receptor, Methyltransferases, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Autism, Neuroscience, 030217 neurology & neurosurgery |
| الوصف: | Large-scale genetic screening has identified KMT5B (SUV420H1), which encodes a histone H4 K20 di- and tri-methyltransferase highly expressed in prefrontal cortex (PFC), as a top-ranking high-risk gene for autism. However, the biological function of KMT5B in the brain is poorly characterized, and how KMT5B deficiency is linked to autism remains largely unknown. Here we knocked down Kmt5b in PFC and examined behavioral and electrophysiological changes, as well as underlying molecular mechanisms. Mice with Kmt5b deficiency in PFC display social deficits, a core symptom of autism, without the alteration of other behaviors. Kmt5b deficiency also produces deficits in PFC glutamatergic synaptic transmission, which is accompanied by the reduced synaptic expression of glutamate receptor subunits and associated proteins. Kmt5b deficiency-induced reduction of H4K20me2 impairs 53BP1-mediated DNA repair, leading to the elevation of p53 expression and its target gene Ddit4 (Redd1), which is implicated in synaptic impairment. RNA-sequencing data indicate that Kmt5b deficiency results in the upregulation of genes enriched in cellular stress response and ubiquitin-dependent protein degradation. Collectively, this study has revealed the functional role of Kmt5b in the PFC, and suggests that Kmt5b deficiency could cause autistic phenotypes by inducing synaptic dysfunction and transcriptional aberration. |
| تدمد: | 1740-634X 0893-133X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fedb9e2f35655bd2d9c6c318be1e0683 https://doi.org/10.1038/s41386-021-01029-y |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....fedb9e2f35655bd2d9c6c318be1e0683 |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 1740634X 0893133X |
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