Increased NMDARs in neurons and glutamine synthetase in astrocytes underlying autistic-like behaviors of Gabrb1-/- mice

作者：Wang, Jing; Gao, Yue; Xiao, Liuyan; Lin, Yanmei; Huang, Lang; Chen, Jinfa; Liang, Guanmei; Li, Weiming; Yi, Wenjuan; Lao, Jianpei; Zhang, Bin; Gao, Tian-Ming; Zhong, Mei; Yang, Xinping

来源：iScience, 2023, 26(8): 107476.

DOI：10.1016/j.isci.2023.107476

• RECEPTOR SUBUNIT GENES
• MORRIS WATER MAZE
• MEMANTINE
• EPILEPSY
• DISABILITIES
• INHIBITION
• ACTIVATION
• DISORDERS
• SYSTEM
• MEMORY

Mutations of the GABA-A receptor subunit b1 (GABRB1) gene are found in autism patients. However, it remains unclear how mutations in Gabrb1 may lead to autism. We generated Gabrb1(-/-) mouse model, which showed autistic-like be-haviors. We carried out RNA-seq on the hippocampus and found glutamatergic pathway may be involved. We further carried out single-cell RNA sequencing on the whole brain followed by qRT-PCR, immunofluorescence, electrophysi-ology, and metabolite detection on specific cell types. We identified the up -regu-lated Glul/Slc38a3 in astrocytes, Grin1/Grin2b in neurons, glutamate, and the ra-tio of Glu/GABA in the hippocampus. Consistent with these results, increased NMDAR-currents and reduced GABAAR-currents in the CA1 neurons were de-tected in Gabrb1(-/-) mice. NMDAR antagonist memantine or Glul inhibitor methi-onine sulfoximine could rescue the abnormal behaviors in Gabrb1(-/-) mice. Our data reveal that upregulation of the glutamatergic synapse pathway, including NMDARs at neuronal synapses and glutamine exported by astrocytes, may lead to autistic-like behaviors.

• 单位
  南方医科大学