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Lrp4 in astrocytes modulates glutamatergic transmission.

ABSTRACT: Neurotransmission requires precise control of neurotransmitter release from axon terminals. This process is regulated by glial cells; however, the underlying mechanisms are not fully understood. We found that glutamate release in the brain was impaired in mice lacking low-density lipoprotein receptor-related protein 4 (Lrp4), a protein that is critical for neuromuscular junction formation. Electrophysiological studies revealed compromised release probability in astrocyte-specific Lrp4 knockout mice. Lrp4 mutant astrocytes suppressed glutamatergic transmission by enhancing the release of ATP, whose level was elevated in the hippocampus of Lrp4 mutant mice. Consequently, the mutant mice were impaired in locomotor activity and spatial memory and were resistant to seizure induction. These impairments could be ameliorated by blocking the adenosine A1 receptor. The results reveal a critical role for Lrp4, in response to agrin, in modulating astrocytic ATP release and synaptic transmission. Our findings provide insight into the interaction between neurons and astrocytes for synaptic homeostasis and/or plasticity.

SUBMITTER: Sun XD

PROVIDER: S-EPMC4961622 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Lrp4 in astrocytes modulates glutamatergic transmission.

Sun Xiang-Dong XD Li Lei L Liu Fang F Huang Zhi-Hui ZH Bean Jonathan C JC Jiao Hui-Feng HF Barik Arnab A Kim Seon-Myung SM Wu Haitao H Shen Chengyong C Tian Yun Y Lin Thiri W TW Bates Ryan R Sathyamurthy Anupama A Chen Yong-Jun YJ Yin Dong-Min DM Xiong Lei L Lin Hui-Ping HP Hu Jin-Xia JX Li Bao-Ming BM Gao Tian-Ming TM Xiong Wen-Cheng WC Mei Lin L

Nature neuroscience 20160613 8

Neurotransmission requires precise control of neurotransmitter release from axon terminals. This process is regulated by glial cells; however, the underlying mechanisms are not fully understood. We found that glutamate release in the brain was impaired in mice lacking low-density lipoprotein receptor-related protein 4 (Lrp4), a protein that is critical for neuromuscular junction formation. Electrophysiological studies revealed compromised release probability in astrocyte-specific Lrp4 knockout m ...[more]

PMID: 27294513

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Project description:IMPORTANCE:Congenital myasthenic syndromes (CMS) are heterogeneous disorders. Defining the phenotypic features, genetic basis, and pathomechanisms of a CMS is relevant to prognosis, genetic counseling, and therapy. OBJECTIVES:To characterize clinical, structural, electrophysiologic, and genetic features of a CMS and to search for optimal therapy. DESIGN, SETTINGS, AND PARTICIPANTS:Two sisters with CMS affecting the limb-girdle muscles were investigated between 2012 and 2014 at an academic medical center by clinical observation, in vitro analysis of neuromuscular transmission, cytochemical and electron microscopy studies of the neuromuscular junction, exome sequencing, expression studies in HEK293 and COS7 cells, and for response to therapy, and they were compared with 15 historical control participants. MAIN OUTCOMES AND MEASURES:We identified the disease gene and mutation, confirmed pathogenicity of the mutation by expression studies, and instituted optimal pharmacotherapy. RESULTS:Quantitative analysis of single EP regions was done for all 15 control participants and microelectrode studies of neuromuscular transmission and ?-bgt binding sites per EP was conducted for 13 control participants. Examination of the older sister's intercostal muscle end plates (EPs) showed them to be abnormally small, with attenuated reactivities for the acetylcholine receptor and acetylcholinesterase. Most EPs had poorly differentiated or degenerate junctional folds, and some appeared denuded of nerve terminals. The amplitude of the EP potential (EPP), the miniature EPP, and the quantal content of the EPP were all markedly reduced. Exome sequencing identified a novel homozygous p.Glu1233Ala mutation in low-density lipoprotein receptor-related protein 4 (LRP4), a coreceptor for agrin to activate muscle-specific tyrosine kinase (MuSK), which is required for EP development and maintenance. Expression studies indicate that the mutation compromises the ability of LRP4 to bind to, phosphorylate, and activate MuSK. Treatment with albuterol sulfate improved the patients' symptoms. A previously identified patient harboring 2 heterozygous mutations in LRP4 had structurally abnormal intercostal EPs but no identifiable defect of neuromuscular transmission at these EPs. CONCLUSIONS AND RELEVANCE:We identified a second CMS kinship harboring mutations in LRP4, identified the mechanisms that impair neuromuscular transmission, and mitigated the disease by appropriate therapy.

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Lrp4 in astrocytes modulates glutamatergic transmission.

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Lrp4 in astrocytes modulates glutamatergic transmission.

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