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

Abstract

Mutations of the GABA-A receptor subunit β1 (<i>GABRB1</i>) gene are found in autism patients. However, it remains unclear how mutations in <i>Gabrb1</i> may lead to autism. We generated <i>Gabrb1</i>^<i>-/-</i> 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 <i>Glul/Slc38a3</i> in astrocytes, <i>Grin1/Grin2b</i> in neurons, glutamate, and the ratio of Glu/GABA in the hippocampus. Consistent with these results, increased NMDAR-currents and reduced GABA_AR-currents in the CA1 neurons were detected in <i>Gabrb1</i>^<i>-/-</i> mice. NMDAR antagonist memantine or <i>Glul</i> inhibitor methionine sulfoximine could rescue the abnormal behaviors in <i>Gabrb1</i>^<i>-/-</i> 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.