title: Lgr4 protein deficiency induces ataxia-like phenotype in mice and impairs long term depression at cerebellar parallel fiber-Purkinje cell synapses.
abstract: Cerebellar dysfunction causes ataxia characterized by loss of balance and coordination. Until now, the molecular and neuronal mechanisms of several types of inherited cerebellar ataxia have not been completely clarified. Here, we report that leucine-rich G protein-coupled receptor 4 (Lgr4/Gpr48) is highly expressed in Purkinje cells (PCs) in the cerebellum. Deficiency of Lgr4 leads to an ataxia-like phenotype in mice. Histologically, no obvious morphological changes were observed in the cerebellum of Lgr4 mutant mice. However, the number of PCs was slightly but significantly reduced in Lgr4(-/-) mice. In addition, in vitro electrophysiological analysis showed an impaired long term depression (LTD) at parallel fiber-PC (PF-PC) synapses in Lgr4(-/-) mice. Consistently, immunostaining experiments showed that the level of phosphorylated cAMP-responsive element-binding protein (Creb) was significantly decreased in Lgr4(-/-) PCs. Furthermore, treatment with forskolin, an adenylyl cyclase agonist, rescued phospho-Creb in PCs and reversed the impairment in PF-PC LTD in Lgr4(-/-) cerebellar slices, indicating that Lgr4 is an upstream regulator of Creb signaling, which is underlying PF-PC LTD. Together, our findings demonstrate for first time an important role for Lgr4 in motor coordination and cerebellar synaptic plasticity and provide a potential therapeutic target for certain types of inherited cerebellar ataxia.
authors: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, and East China Normal University, Shanghai 200241, China.
authors: Xin
authors: X
authors: Guan
authors: Key Laboratory of Brain Functional Genomics, Ministry of Education, East China Normal University, Shanghai 200241, China, and.
authors: Yanhong
authors: Y
authors: Duan
authors: Key Laboratory of Brain Functional Genomics, Ministry of Education, East China Normal University, Shanghai 200241, China, and.
authors: Qingwen
authors: Q
authors: Zeng
authors: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, and East China Normal University, Shanghai 200241, China.
authors: Hongjie
authors: H
authors: Pan
authors: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, and East China Normal University, Shanghai 200241, China.
authors: Yu
authors: Y
authors: Qian
authors: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, and East China Normal University, Shanghai 200241, China. Electronic address: dlli@bio.ecnu.edu.cn.
authors: Dali
authors: D
authors: Li
authors: Key Laboratory of Brain Functional Genomics, Ministry of Education, East China Normal University, Shanghai 200241, China, and. Electronic address: xhcao@brain.ecnu.edu.cn.
authors: Xiaohua
authors: X
authors: Cao
authors: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, and East China Normal University, Shanghai 200241, China; Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030. Electronic address: myliu@bio.ecnu.edu.cn.
authors: Mingyao
authors: M
authors: Liu
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002524:Cerebellar Ataxia / Q000235:genetics / Q000503:physiopathology; D002525:Cerebellar Cortex / Q000503:physiopathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D036881:Long-Term Synaptic Depression; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D010364:Pattern Recognition, Visual; D010641:Phenotype; D011597:Psychomotor Performance; D011689:Purkinje Cells / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics*; D045442:Rotarod Performance Test; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C496200:LGR4 protein, mouse; D043562:Receptors, G-Protein-Coupled
keywords: 7-Helix Receptor; Ataxia; Cerebellum; Signal Transduction; cAMP-response Element-binding Protein (Creb)