PMID- 34646371 OWN - NLM STAT- MEDLINE DCOM- 20220207 LR - 20220207 IS - 1838-7640 (Electronic) IS - 1838-7640 (Linking) VI - 11 IP - 19 DP - 2021 TI - Upregulated NMDAR-mediated GABAergic transmission underlies autistic-like deficits in Htr3a knockout mice. PG - 9296-9310 LID - 10.7150/thno.60531 [doi] AB - Mutations in serotonin pathway genes, especially the serotonergic receptor subunit gene HTR3A, are associated with autism. However, the association of HTR3A deficiency with autism and the underlying mechanisms remain unknown. Methods: The Htr3a knockout (KO) mice were generated using transcription activator-like effector nuclease technology. Various behavior tests, including social interaction, social approach task, olfactory habituation/dishabituation, self-grooming, novel object recognition, contextual fear conditioning, elevated plus maze, open field and seizure susceptibility, were performed to assess the phenotypes. Transcriptome sequencing was carried out to search for molecular network and pathways underlying the phenotypes. Electrophysiological recordings, immunoblotting, immunofluorescence staining, immunoprecipitation, and quantitative real-time PCR were performed to verify the potential mechanisms. The N-methyl-D-aspartate receptor (NMDAR) antagonist memantine was used to treat the KO mice for rescuing the phenotypes. Results: The Htr3a KO mouse model showed three phenotypic domains: autistic-like behaviors (including impaired social behavior, cognitive deficits, and increased repetitive self-grooming), impaired memory, and attenuated susceptibility to pentylenetetrazol-induced seizures. We observed enhanced action potential-driven gamma-aminobutyric acid-ergic (GABAergic) transmission in pyramidal neurons and decreased excitatory/inhibitory (E/I) ratio using the patch-clamp recording. Transcriptome sequencing on the hippocampus revealed the converged pathways of the dysregulated molecular networks underlying three phenotypic domains with upregulation of NMDAR. We speculated that Htr3a KO promotes an increase in GABA release through NMDAR upregulation. The electrophysiological recordings on hippocampal parvalbumin-positive (PV(+)) interneuron revealed increased NMDAR current and NMDAR-dependent excitability. The NMDAR antagonist memantine could rescue GABAergic transmission in the hippocampus and ameliorate autistic-like behaviors of the KO mice. Conclusion: Our data indicated that upregulation of the NMDAR in PV(+) interneurons may play a critical role in regulating GABAergic input to pyramidal neurons and maybe involve in the pathogenesis of autism associated with HTR3A deficiency. Therefore, we suggest that the NMDAR system could be considered potential therapeutic target for autism. CI - (c) The author(s). FAU - Huang, Lang AU - Huang L AD - Center for Genetics and Developmental Systems Biology, Department of Obstetrics & Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. AD - 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, Guangdong Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. FAU - Wang, Jing AU - Wang J AD - Center for Genetics and Developmental Systems Biology, Department of Obstetrics & Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. AD - 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, Guangdong Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. FAU - Liang, Guanmei AU - Liang G AD - Center for Genetics and Developmental Systems Biology, Department of Obstetrics & Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. AD - 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, Guangdong Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. AD - Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. FAU - Gao, Yue AU - Gao Y AD - Center for Genetics and Developmental Systems Biology, Department of Obstetrics & Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. AD - 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, Guangdong Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. AD - Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. FAU - Jin, Shi-Yang AU - Jin SY AD - 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, Guangdong Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. FAU - Hu, Jian AU - Hu J AD - 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, Guangdong Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. FAU - Yang, Xiaoxue AU - Yang X AD - Center for Genetics and Developmental Systems Biology, Department of Obstetrics & Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. FAU - Lao, Jianpei AU - Lao J AD - Center for Genetics and Developmental Systems Biology, Department of Obstetrics & Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. AD - 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, Guangdong Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. AD - Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. FAU - Chen, Jinfa AU - Chen J AD - Center for Genetics and Developmental Systems Biology, Department of Obstetrics & Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. AD - 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, Guangdong Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. AD - Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. FAU - Luo, Zhou-Cai AU - Luo ZC AD - 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, Guangdong Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. FAU - Fan, Cuixia AU - Fan C AD - Center for Genetics and Developmental Systems Biology, Department of Obstetrics & Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. AD - Institute of Neuroscience and Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China. FAU - Xiong, Li AU - Xiong L AD - Center for Genetics and Developmental Systems Biology, Department of Obstetrics & Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. AD - 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, Guangdong Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. FAU - Zhu, Xinhong AU - Zhu X AD - 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, Guangdong Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. FAU - Gao, Tian-Ming AU - Gao TM AD - 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, Guangdong Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. FAU - Zhong, Mei AU - Zhong M AD - Center for Genetics and Developmental Systems Biology, Department of Obstetrics & Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. FAU - Yang, Xinping AU - Yang X AD - Center for Genetics and Developmental Systems Biology, Department of Obstetrics & Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. AD - 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, Guangdong Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. AD - Department of Bioinformatics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210907 PL - Australia TA - Theranostics JT - Theranostics JID - 101552395 RN - 0 (Htr3a protein, mouse) RN - 0 (Nerve Tissue Proteins) RN - 0 (Receptors, GABA) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 0 (Receptors, Serotonin, 5-HT3) RN - 333DO1RDJY (Serotonin) RN - 56-12-2 (gamma-Aminobutyric Acid) SB - IM MH - Animals MH - Autism Spectrum Disorder/*genetics/metabolism MH - Brain/metabolism MH - Disease Models, Animal MH - GABAergic Neurons/*metabolism MH - Gene Expression/genetics MH - Hippocampus/metabolism MH - Male MH - Memory/physiology MH - Mice MH - Mice, Knockout MH - Nerve Tissue Proteins/metabolism MH - Pyramidal Cells/metabolism MH - Receptors, GABA/genetics MH - Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors MH - Receptors, Serotonin, 5-HT3/*genetics/metabolism MH - Seizures/physiopathology MH - Serotonin/metabolism MH - Social Behavior MH - Transcriptome/genetics MH - gamma-Aminobutyric Acid/metabolism PMC - PMC8490518 OTO - NOTNLM OT - Htr3a OT - NMDAR OT - autism OT - interactome OT - transcriptome COIS- Competing Interests: The authors have declared that no competing interest exists. EDAT- 2021/10/15 06:00 MHDA- 2022/02/08 06:00 PMCR- 2021/01/01 CRDT- 2021/10/14 06:35 PHST- 2021/03/17 00:00 [received] PHST- 2021/08/28 00:00 [accepted] PHST- 2021/10/14 06:35 [entrez] PHST- 2021/10/15 06:00 [pubmed] PHST- 2022/02/08 06:00 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - thnov11p9296 [pii] AID - 10.7150/thno.60531 [doi] PST - epublish SO - Theranostics. 2021 Sep 7;11(19):9296-9310. doi: 10.7150/thno.60531. eCollection 2021.