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

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.