梅林

大脑包含数十亿个神经细胞或神经元，它们接收和整合来自周围环境的信号，最终控制机体做出反应。神经元的电活动往往是通过突触，即神经元之间或神经元与靶细胞之间的接触实现的。神经递质从突触前膜释放并最终激活突触后膜上的受体，从而建立神经元之间的通讯。因此，突触是神经回路的基本单位，使复杂的行为得以完成。

我们实验室的研究集中在突触形成、神经传递和突触可塑性的机制上。我们的目标是更好地了解这些过程，并开发精神疾病（如精神分裂症、自闭症和抑郁症）以及神经系统疾病（如神经肌肉疾病和癫痫）的潜在治疗策略。曾在我们实验室工作学习的二十多名博士或博士后已先后建立了自己的实验室。

神经肌肉接头（NMJ）的形成和疾病

人们的日常活动中，如起床、走路、吃饭、饮水和坐立，都需要NMJ发挥正常功能。NMJ是运动神经元和肌肉纤维之间的外周突触，对于精确且快速的控制肌肉收缩至关重要。这种长久以来被神经科学家认可的经典化学突触早已成为突触结构和功能的信息模型。尽管众多NMJ突触成分已被鉴定出，但它们到底如何组装并最终形成了NMJ尚不清楚。目前，人们已知NMJ的形成需要agrin（一种来自运动神经元的营养因子）和MuSK（一种可被agrin激活的跨膜酪氨酸激酶）。然而，Agrin 不与 MuSK 直接互做。在此基础上，我们实验室率先确定了LRP4为agrin的受体（直接互作），并通过解决agrin-LRP4复合物的晶体结构揭示了信号如何从agrin转移到MuSK的机制。在针对重症肌无力患者开展的研究中，我们鉴定了针对LRP4和agrin的抗体，并证明它们与重症肌无力有关。这些抗体被用作诊断重症肌无力的新型生物标志物。与此同时，我们还揭示了rapsyn，一种经典的突触后支架蛋白，可通过液-液相分离的方式形成无膜缩合物，帮助AChR聚集及NMJ形成。此外，我们的研究还进一步证实了rapsyn具有NMJ形成所需的E3连接酶活性，其酶活对NMJ的发生、维持和再生至关重要。

神经调节蛋白 1 （NRG1） 和 ErbB4 信号在兴奋性/抑制性平衡中的应用

神经元主要有两种类型：使用谷氨酸作为神经递质的兴奋性（也称为投射或锥体）神经元以及释放GABA的抑制性中间神经元（IN），占大脑中总神经元比例的大约15%-20%。目前人们已知中间神经元可通过前馈和反馈抑制控制投射神经元的发放。中间神经元增加了皮层网络的计算能力，并同步了对振荡活动至关重要的局部和远端皮层环路。研究表明，GABA信号传导的中断与脑部疾病有关，包括自闭症、抑郁症、智力残疾、Rett综合征和精神分裂症等。我们实验室的研究已经证明了NRG1及其受体ErbB4对大脑中的GABA活性至关重要。我们发现，NRG1由锥体神经元以活动依赖性方式产生。它与中间神经元中的ErbB4结合以促进GABA释放，从而抑制锥体神经元的活动。这种稳态通路对诸多大脑功能尤为关键，包括工作记忆和恐惧。此外，NRG1和ErbB4都是重度抑郁症和精神分裂症的风险基因。我们的研究为众多严重的脑部疾病的病理生理机制提供了见解。

脑部疾病的病理机制

由于许多精神疾病缺乏明确的病理特征，因此在病理生理机制方面人们知之甚少。随着遗传学分析的进步，遗传学家目前已初步筛查到部分脑部疾病的多种风险基因。通过研究Erbin，TMEM108，NRG3，Caspr3和Cullin 3的缺乏和/或新生突变的小鼠模型（下图，左侧野生型，右侧Cullin 3缺陷小鼠），我们实验室陆续揭示了它们在神经发育和神经传递中的生理功能，并提供了对精神分裂症、重度抑郁症和自闭症的病理生理机制的见解。

2023

1. R. Cao*, P. Chen*, H.S. Wang*, H. Jing, H. Zhang, G. Xing, B. Luo, J. Pan, Z. Yu, W.C. Xiong, L. Mei. Intrafusal-fiber LRP4 for Muscle Spindle Formation and Maintenance in Adult and Aged Animals. Nature Communications. 2023. doi.org/10.1038/s41467-023-36454-8. (*co-first).

2. E.D. Kosco*, H. Jing, P. Chen, W.C. Xiong, L. Mei. DOK7 Promotes NMJ Regeneration After Nerve Injury. Molecular Neurobiology. 2023. doi.org/10.1007/s12035-022-03143-4.

2022

1. Z.T. Tan*, Z. Liu*, Y. Liu, H. Robinson, T.W. Lin, W.C. Xiong, L. Mei. An ErbB4-Positive Neuronal Network in the Olfactory Bulb for Olfaction. The Journal of Neuroscience. 43(34): 6518-6535, 2022. doi.org/10.1523/JNEUROSCI.0131-22.2022. PMID: 35853717. (Cover; *co-first).

2. H.S. Wang*, W.B. Chen*, Z.Q. Dong*, G. Xing, W.P. Cui, L.L. Yao, W.J. Zou, H.L. Robinson, Y. Bian, Z. Liu, K. Zhao, B. Luo, N.N. Gao, H.S. Zhang, X. Ren, Z. Yu, J. Meixiong, W.C. Xiong, L. Mei. A novel spinal neuron connection for heat sensation. Neuron. 110(14): 2315-2333.e6, 2022 May 6. doi: 10.1016/j.neuron.2022.04.021. PMID: 35561677. (*co-first)

3. H.L. Robinson, Z. Tan, I. Santiago-Marrero, E.P. Arzola, T.V. Dong, W.C. Xiong and L. Mei. Neuregulin 1 and ErbB4 Kinase Actively Regulate Sharp Wave Ripples in the Hippocampus. The Journal of Neuroscience. 42(3): 390-404, 2022. doi: 10.1523/JNEUROSCI.1022-21.2021. PMID 34844988. (Cover).

2021

1. W.B. Chen*, B. Luo*, N.N. Gao*, H.W. Li, H.S. Wang, L. Li, W.P. Cui, L. Zhang, D. Sun, F. Liu, Z.Q. Dong, H.S. Zhang, H. B. Su, W.C. Xiong, and L. Mei. Neddylation of Nav1.1 is critical for the excitability of interneurons and seizure prevention. J. Clin. Invest. (*co-first) 131(8):e136956. doi.org/10.1172/JCI136956, 2021 (Commentary by S.C. Cannon, Epilepsy channelopathies go neddy: stabilizing NaV1.1 channels by neddylation. JCI 131(8):e148370). PMID: 33651714 / PMCID: PMC8262483.

2. H. Wang*, W. Cui*, W. Chen*, F. Liu, Z. Dong, G. Xing, B. Luo, N. Gao, W.-J. Zou, K. Zhao, H. Zhang, X. Ren, Z. Yu, H.L. Robinson, Z. Liu, W.C. Xiong, L. Mei. The laterodorsal tegmentum-ventral tegmental area circuit controls depression-like behaviors by activating ErbB4 in DA neurons. Molecular Psychiatry. 2021 May 14. doi: 10.1038/s41380-021-01137-7. PMID: 33990773. (Cover, *co-first)

3. G. Xing, H. Jing, Z. Yu, P. Chen, H. Wang, W.C Xiong, and L. Mei. Membraneless condensates by Rapsn phase separation as a platform for neuromuscular junction formation. Neuron. 109:1963-1978, 2021 (Cover and Preview by Bai and Zhang, Neuron, 1907-1909, 2021). PMID: 34033754 / PMCID: PMC8217331.

4. W. Cui*, N. Gao*, Z. Dong, C. Shen, H. Zhang, B. Luo, P. Chen, D. Comoletti, H. Jing, H. Wang, H. Robinson, W.C. Xiong, and L. Mei. In-trans neuregulin3-Caspr3 interaction controls DA axonal bassoon cluster development. Current Biology 2021 Aug 9;31(15):3330-3342.e7. doi: 10.1016/j.cub.2021.05.045. PMID: 34143959.

5. Z. Yu, M. Zhang, H. Jing, P. Chen, R. Cao, P. Pan, B. Luo, Y. Yu, B.M. Quarles, W.C. Xiong, M.H. Rivner, and L. Mei. Characterization of LRP4/agrin Antibodies from a Patient with Myasthenia Gravis. Neurology 2021 Sep 7;97(10):e975-e987. (Preview by Lisak, Neurology Sep 07, 2021; 97 (10))  Doi: 10.1212/WNL.0000000000012463. PMID: 34233932.

2020

1. Z. Dong*, W. Chen*, C. Chen, H. Wang, W. Cui, Z. Tan, H. Robinson, N. Gao, B. Luo, L. Zhang, K. Zhao, W.C. Xiong and L. Mei. CUL3 Deficiency Causes Social Deficits and Anxiety-like Behaviors by Impairing Excitation-Inhibition Balance through the Promotion of Cap-Dependent Translation. Neuron105: 475-490, 2020 (Cover; Preview by Chen & Maher, Neuron, 105:398-399, 2020). PMID:31780330 / PMCID:PMC7007399. Doi: 10.1016/j.neuron.2019.10.035. (*co-first)

2. H. Zhang, W. Chen, Z. Tan, L. Zhang, Z. Dong, W. Cui, K. Zhao, H. Wang, H. Jing, R. Cao, C. Kim, J.G. Safar, W.-C. Xiong and L. Mei. A role of low-density lipoprotein receptor-related protein 4 (LRP4) in astrocytic Aβ clearance. J. Neurosci., 2020 Jul 8;40(28):5347:5361. Doi: 10.1523/jneurosci.0250-20.2020. Epub 2020 May 26. PMID:32457076 / PMCID:PMC7343327 (JC by J. Cavieres-Lepe and N. Stuardo, J. Neurosci. 41:3749-3751).

3. N. Gao, K. Zhao, Y. Cao, X. Ren, H. Jing, G. Xing, W.-C. Xiong, and Lin Mei. A role of lamin A/C in preventing neuromuscular junction decline in mice. J. Neurosci.40:7203-7215, 2020 (Cover). PMID: 32817327 / PMCID: PMC7534915. Doi: 10.1523/JNEUROSCI.0443-20.2020.

4. M.H. Rivner, B.M. Quarles, J.-X. Pan, Z. Yu, J.F. Howard Jr, A. Corse, M.M. Dimachkie, C. Jackson, T. Vu, G. Small, R.P. Lisak, J. Belsh, I. Lee, R.J. Nowak, V. Baute, S. Scelsa, J.A. Fernandes, Z. Simmons, A. Swenson, R. Barohn, R.B. Sanka, C. Gooch, E. Ubogu, J. Caress, M. Pasnoor, H. Xu, L. Mei. Clinical features of LRP4/agrin-antibody – positive myasthenia gravis: A multicenter study. Muscle & Nerve 62:333–343, 2020. PMID: 32483837 / PMCID: PMC7496236. Doi: 10.1002/mus.26985.

5. L. Zhang, H. Jing, H. Li, W. Chen, B. Luo, H-S. Zhang, Z-Q. Dong, L. Li, H-B. Su, W-C. Xiong and L. Mei. Neddylation is critical to cortical development by regulating Wnt/b-catenin signaling. Proc. Nat. Acad. Sci. USA. 117:26448-26459, 2020. PMID: 33020269 / PMCID: PMC7584916 Doi: 10.1073/pnas.2005395117.

2019

1. H. Zhang, A. Sathyamurthy, F. Liu, L. Li, L. Zhang, Z. Dong, W. Cui, X. Sun, K. Zhao, H. Wang, H.-Y. H. Ho, W.C. Xiong, L. Mei. Agrin-Lrp4-Ror2 signaling regulates adult hippocampal neurogenesis in mice. eLife 8:e45303 DOI: 10.7554/eLife.45303, 2019. PMID:31268420 / PMCID:PMC6650252.

2. G. Xing, H. Jing, L. Zhang, Y. Cao, L. Li, K. Zhao, Z. Dong, W. Chen, H. Wang, R. Cao, W.C. Xiong, and L. Mei. A mechanism in agrin signaling revealed by a prevalent Rapsyn mutation in congenital myasthenic syndrome. eLife 8:e49180, 2019. PMID:31549961 / PMCID:PMC6779466 Doi: 10.7554/eLife.49180.

2018

1. Y.-N. Wang, D. Figueiredo, X.-D. Sun, Z.-Q. Dong, W.-B. Chen, W.-P. Cui, F. Liu, H.-S. Wang, H.-W. Li, H. Robinson, E.-K. Fei, B.-X. Pan, B-M Li, W-C Xiong and L. Mei. Controlling of glutamate release by neuregulin3 via inhibiting the assembly of SNARE-complex. Proc. Nat. Acad. Sci. 115:2508-2513, 2018. PMID:29463705 / PMCID:PMC5877931 DOI: 10.1073/pnas.1716322115.

2. T.W. Lin, Z. Tan, A. Barik, D. Yin, E. Brudvik, H. Wang, W.C. Xiong, L. Mei. Regulation of Synapse Development by Vgat Deletion from ErbB4-Positive Interneurons. J. Neurosci. 38:2533-2550, 2018. PMID:29431653 / PMCID:PMC5858595 DOI: 10.1523/JNEUROSCI.0669-17.2018.

3. M. Yan, Z. Liu, E. Fei, W. Chen, X. Lai, B. Luo, P. Chen, H. Jing, J. Pan, M. Rivner, W.C. Xiong, and L. Mei. Induction of anti-agrin antibodies causes myasthenia gravis in mice. Neuroscience, 373:113-121, 2018. PMID:29339325 / PMCID:PMC5942223 Doi: 10.1016/j.neuroscience.2018.01.015.

4. Z. Tan*, H. Robinson*, D. Yin, Y. Liu, F. Liu, H. Wang, T.W. Lin, G. Xing, W.C. Xiong, L. Mei. Dynamic ErbB4 activity in hippocampal-prefrontal synchrony and top-down attention in rodents. Neuron 98:380-393, 2018. PMID:29628188 / PMCID:PMC5909841 Doi: 10.1016/j.neuron.2018.03.018 (*co-first).

5. C. Shen*,**, L. Li**, K. Zhao**, L. Bai, A. Wang, X. Shu, Y. Xiao, J. Zhang, K. Zhang, T. Hui, W. Chen, B. Zhang, W. Hsu, W.-C. Xiong, L. Mei*. Motoneuron Wnts regulate neuromuscular junction development. eLife. 7, 2018 pii: e34625. doi: 10.7554/eLife.34625 (*co-corresponding; **co-first). PMID:30113308.

6. K. Zhao*, C. Shen,*,** L. Li, H. Wu, G. Xing, Z. Dong, W. Chen, H. Zhang, J. Pan, H. Wang, W. Cui, X.D. Sun, S. Li, X. Li, X. Huang, W.C. Xiong, and L. Mei**. Sarcoglycan Alpha Mitigates Neuromuscular Junction Decline in Aged Mice by Stabilizing Lrp4. J. Neurosci.38:8860-8873, 2018. (Cover) (*equal contributing; **co-corresponding). PMID:30171091 / PMCID:PMC6181315 Doi: 10.1523/JNEUROSCI.0860-18.2018.

7. H. Wang,* F. Liu,* W. Chen,* X. Sun, W. Cui, Z. Dong, K. Zhao, H. Zhang, H. Li, G. Xing, E. Fei, B.-X. Pan, B.-M. Li, W.-C. Xiong, Lin Mei. Genetic recovery of ErbB4 in adulthood partially restores brain functions in null mice. PNAS115:13105-13110, 2018. PMID:30498032 / PMCID:PMC6304932 Doi: 10.1073/pnas.1811287115. (*co-first)

Selected Recent Reviews

1. G. Xing, W.C. Xiong, L. Mei. Rapsyn as a signaling and scaffolding molecule in NMJ formation and maintenance. Neurosci. Lett. 731:1350132, 2020

2. M Yan, GL Xing, WC Xiong, L Mei. Agrin and LRP4 antibodies as new biomarkers of myasthenia gravis. Ann. New York Acad. Sci. 1413: 126-135, 2018.

3. L. Li, W.C. Xiong, L. Mei, Neuromuscular junction formation, aging, and disorders. Ann. Rev. Physiol. 2018

4. Mei and K.-A. Nave, A neuregulin and ErbB network in the nervous system. Neuron 83:27-49, 2014

5. Wu, Wen C. Xiong, L. Mei. To build a synapse: Signaling pathways in neuromuscular junction assembly. Development 137:1017-1033, 2010

6. Mei and W.C. Xiong, Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nature Rev. Neurosci. 9:437-452, 2008.