Ablation of TFR1 in Purkinje Cells Inhibits mGlu1 Trafficking and Impairs Motor Coordination, But Not Autistic-Like Behaviors
Ablation of TFR1 in Purkinje Cells Inhibits mGlu1 Trafficking and Impairs Motor Coordination, But Not Autistic-Like Behaviors
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浦肯野细胞中 TFR1 的消除会抑制 mGlu1 运输并损害运动协调性，但不会损害类似自闭症的行为
DOI：
10.1523/jneurosci.1223-17.2017
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发表时间：
2017-11
期刊：
影响因子：
--
通讯作者：
Ying Shen
中科院分区：
文献类型：
--
作者：
Jia-Huan Zhou;Xin-Tai Wang;Liang Zhou;Lin Zhou;Fang-Xiao Xu;Li-Da Su;Hao Wang;Fan Jia;Fu-Qiang Xu;Gui-Quan Chen;Chris I. De Zeeuw;Ying Shen
1组代谢性谷氨酸受体（mGlu1/5s）对突触的形成至关重要，并参与突触的LTP和LTD。mGlu1/5信号的改变在认知障碍、神经退行性疾病和精神疾病中都有记载，但其调节的潜在机制尚不清楚。在这里，我们报道了转铁蛋白受体1 (TFR1)，一种网格蛋白复合物的跨膜蛋白，调节雄性小鼠小脑浦肯野细胞（PCs）中mGlu1的运输。我们发现，TFR1的条件敲除不会影响PCs的细胞结构，但会降低突触中的mGlu1表达。TFR1的这种调控与Rab8和Rab11的调控一致，它们分别调节mGlu1的内化和循环。TFR1可以结合Rab蛋白并促进其在突触的表达。PC烧蚀TFR1抑制平行纤维- PC LTD，而平行纤维- ltp和PC固有兴奋性不受影响。最后，我们证明了TFR1的PC消融损害了小鼠的运动协调，但不影响社交行为。总之，这些发现强调了TFR1在调节mGlu1贩运中的重要性，并表明mGlu1-和mGlu1依赖性平行纤维- ltd与运动协调的调节有关，但与自闭症行为无关。1组代谢性谷氨酸受体（mGlu1/5）信号改变在认知障碍、神经退行性疾病和精神疾病中有文献记载。最近的研究表明浦肯野细胞（PCs）中mGlu1信号的改变可能不仅与运动学习有关，还与自闭症样行为有关。我们发现转铁蛋白受体1 （TFR1）的条件敲除通过在细胞质中拴住Rab8和Rab11来减少突触mGlu1。PC烧蚀TFR1抑制平行纤维- PC LTD，而平行纤维- PC LTP和PC固有兴奋性不变。TFR1flox/flox患儿运动协调能力受损，但社交行为正常；pCP2-cre老鼠。我们的数据揭示了mGlu1的运输和突触表达的一个新的调节因子，并表明mGlu1依赖性LTD与运动协调有关，但与自闭症样行为无关。
Group 1 metabotropic glutamate receptors (mGlu1/5s) are critical to synapse formation and participate in synaptic LTP and LTD in the brain. mGlu1/5 signaling alterations have been documented in cognitive impairment, neurodegenerative disorders, and psychiatric diseases, but underlying mechanisms for its modulation are not clear. Here, we report that transferrin receptor 1 (TFR1), a transmembrane protein of the clathrin complex, modulates the trafficking of mGlu1 in cerebellar Purkinje cells (PCs) from male mice. We show that conditional knock-out of TFR1 in PCs does not affect the cytoarchitecture of PCs, but reduces mGlu1 expression at synapses. This regulation by TFR1 acts in concert with that by Rab8 and Rab11, which modulate the internalization and recycling of mGlu1, respectively. TFR1 can bind to Rab proteins and facilitate their expression at synapses. PC ablation of TFR1 inhibits parallel fiber–PC LTD, whereas parallel fiber–LTP and PC intrinsic excitability are not affected. Finally, we demonstrate that PC ablation of TFR1 impairs motor coordination, but does not affect social behaviors in mice. Together, these findings underscore the importance of TFR1 in regulating mGlu1 trafficking and suggest that mGlu1- and mGlu1-dependent parallel fiber–LTD are associated with regulation of motor coordination, but not autistic behaviors. SIGNIFICANCE STATEMENT Group 1 metabotropic glutamate receptor (mGlu1/5) signaling alterations have been documented in cognitive impairment, neurodegenerative disorders, and psychiatric diseases. Recent work suggests that altered mGlu1 signaling in Purkinje cells (PCs) may be involved in not only motor learning, but also autistic-like behaviors. We find that conditional knock-out of transferrin receptor 1 (TFR1) in PCs reduces synaptic mGlu1 by tethering Rab8 and Rab11 in the cytosol. PC ablation of TFR1 inhibits parallel fiber–PC LTD, whereas parallel fiber–PC LTP and PC intrinsic excitability are intact. Motor coordination is impaired, but social behaviors are normal in TFR1flox/flox;pCP2-cre mice. Our data reveal a new regulator for trafficking and synaptic expression of mGlu1 and suggest that mGlu1-dependent LTD is associated with motor coordination, but not autistic-like behaviors.
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影响因子：
16.6
作者：
Wang X;Bey AL;Katz BM;Badea A;Kim N;David LK;Duffney LJ;Kumar S;Mague SD;Hulbert SW;Dutta N;Hayrapetyan V;Yu C;Gaidis E;Zhao S;Ding JD;Xu Q;Chung L;Rodriguiz RM;Wang F;Weinberg RJ;Wetsel WC;Dzirasa K;Yin H;Jiang YH
通讯作者：
Jiang YH
DOI：
10.1146/annurev.pharmtox.011008.145533
发表时间：
2010
影响因子：
12.5
作者：
Niswender CM;Conn PJ
通讯作者：
Conn PJ
影响因子：
16.2
作者：
Yang S;Huang S;Gaertig MA;Li XJ;Li S
通讯作者：
Li S
影响因子：
2.7
作者：
Gantois, Ilse;Pop, Andreea S.;Willemsen, Rob
通讯作者：
Willemsen, Rob
影响因子：
16.6
作者：
Peter S;Ten Brinke MM;Stedehouder J;Reinelt CM;Wu B;Zhou H;Zhou K;Boele HJ;Kushner SA;Lee MG;Schmeisser MJ;Boeckers TM;Schonewille M;Hoebeek FE;De Zeeuw CI
通讯作者：
De Zeeuw CI