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; Tian-Ming Gao; Mei Zhong; Xinping Yang

doi:10.1016/j.isci.2023.107476

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

iScience. 2023 Jul 25;26(8):107476. doi: 10.1016/j.isci.2023.107476. eCollection 2023 Aug 18.

Authors

Jing Wang^{1

2

3}, Yue Gao^{1

2

3

4

5

6}, Liuyan Xiao^{1

2

3

4

5

6}, Yanmei Lin^{1

2

3

7}, Lang Huang^{5

6}, Jinfa Chen^{1

2

3

7

4

5}, Guanmei Liang^{1

2

3

4}, Weiming Li⁷, Wenjuan Yi^{1

2

3}, Jianpei Lao^{1

2

3

7

4

5}, Bin Zhang⁷, Tian-Ming Gao^{5

6}, Mei Zhong², Xinping Yang^{1

2

3

7

4

5}

Affiliations

¹ Center for Genetics and Developmental Systems Biology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
² Department of Obstetrics & Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
³ State Key Laboratory of Organ Failure Research, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
⁴ Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
⁵ Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
⁶ Guangdong Key Laboratory of Psychiatric Disorders, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
⁷ Department of Psychiatry, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.

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_AR-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.

Keywords: Behavioral neuroscience; Neuroscience; Omics; Transcriptomics.