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.
Highlights
Cerebellar dysfunction leads to ataxia characterized by loss of balance and coordination
We performed the accelerating rotarod test, which requires good motor coordination (38) on Lgr4Ϫ/Ϫ mice as well as wild-type littermate controls. Both wild-type and mutant mice improved their performance over a 4-day training session, Lgr4Ϫ/Ϫ mice showed a significantly shorter latency to fall compared with wild-type littermates (Fig. 2A), suggesting that motor coordination was impaired in Lgr4Ϫ/Ϫ mice
As the cAMP-cAMP-responsive element-binding protein (Creb) cascade plays a critical role in the regulation of long term depression (LTD) at PF-Purkinje cells (PCs) synapses (8), we investigated this pathway in Lgr4 mutants
Summary
Cerebellar dysfunction leads to ataxia characterized by loss of balance and coordination. Results: Lgr deficiency mice show an ataxia-like phenotype and impaired long term depression in cerebellum. Conclusion: Lgr4-mediated cAMP-Creb signaling is required for motor coordination and cerebellar synaptic plasticity. Our findings demonstrate for first time an important role for Lgr in motor coordination and cerebellar synaptic plasticity and provide a potential. Pharmacological treatment of slices with forskolin successfully recovered the reduced p-Creb levels and restored LTD to levels seen in wild-type mice To our knowledge, these results demonstrated for the first time that Lgr plays an essential role in cerebellum-related motor coordination and PF-PC LTD
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