Increased NMDARs in neurons and glutamine synthetase in astrocytes underlying autistic-like behaviors of Gabrb1−/− mice
Jing Wang, Yue Gao, Liuyan Xiao, Yanmei Lin, Lang Huang, Jinfa Chen, Guanmei Liang, Weiming Li, Wenjuan Yi, Jianpei Lao, Bin Zhang, Tianming Gao, Mei Zhong, Xinping Yang
Abstract
Mutations of the GABA-A receptor subunit β1 ( 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 behaviors. 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, electrophysiology, and metabolite detection on specific cell types. We identified the up-regulated Glul/Slc38a3 in astrocytes, Grin1/Grin2b in neurons, glutamate, and the ratio of Glu/GABA in the hippocampus. Consistent with these results, increased NMDAR-currents and reduced GABA A R-currents in the CA1 neurons were detected in Gabrb1 −/− mice. NMDAR antagonist memantine or Glul inhibitor methionine 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.