Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures
| Autor: | Kaijie Ma, Zhen Yan, Jamal B Williams, Luye Qin, Tiaotiao Liu, Qing Cao, Tao Tan |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Autism Spectrum Disorder Science General Physics and Astronomy Prefrontal Cortex Inhibitory postsynaptic potential General Biochemistry Genetics and Molecular Biology Article Epigenesis Genetic Histones Epilepsy Glutamatergic Mice Risk Factors Seizures Intellectual Disability Medicine Premovement neuronal activity Animals Homeostasis Humans Autistic Disorder Prefrontal cortex Gene knockdown Multidisciplinary business.industry Pyramidal Cells Brain General Chemistry Histone-Lysine N-Methyltransferase Autism spectrum disorders medicine.disease Cellular neuroscience DNA-Binding Proteins Mice Inbred C57BL Disease Models Animal nervous system Autism Female business Haploinsufficiency Neuroscience |
| Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | ASH1L, a histone methyltransferase, is identified as a top-ranking risk factor for autism spectrum disorder (ASD), however, little is known about the biological mechanisms underlying the link of ASH1L haploinsufficiency to ASD. Here we show that ASH1L expression and H3K4me3 level are significantly decreased in the prefrontal cortex (PFC) of postmortem tissues from ASD patients. Knockdown of Ash1L in PFC of juvenile mice induces the downregulation of risk genes associated with ASD, intellectual disability (ID) and epilepsy. These downregulated genes are enriched in excitatory and inhibitory synaptic function and have decreased H3K4me3 occupancy at their promoters. Furthermore, Ash1L deficiency in PFC causes the diminished GABAergic inhibition, enhanced glutamatergic transmission, and elevated PFC pyramidal neuronal excitability, which is associated with severe seizures and early mortality. Chemogenetic inhibition of PFC pyramidal neuronal activity, combined with the administration of GABA enhancer diazepam, rescues PFC synaptic imbalance and seizures, but not autistic social deficits or anxiety-like behaviors. These results have revealed the critical role of ASH1L in regulating synaptic gene expression and seizures, which provides insights into treatment strategies for ASH1L-associated brain diseases. ASH1L haploinsufficiency is strongly linked to autism, despite the unknown mechanism. Here, the authors show that ASH1L deficiency in prefrontal cortex causes the downregulation of synaptic genes, leading to seizures, which is rescued by chemogenetic and pharmacological restoration of excitation/inhibition balance. |
| Databáze: | OpenAIRE |
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