自閉症的神經形態及迴路生成研究

我們實驗室致力於探討基因如何控制神經元的形態和活動， 從而調節神經迴路的形成和動物行為。因為自閉症譜系障 礙（簡稱自閉症）源於異常的神經發育，進而導致異常的神 經迴路，所以我們以自閉症的致病基因為範例，研究控制神 經迴路的分子機制，探索腦的奧妙。最近的證據進一步表 明，自閉症致病基因可能具有演化上保守的功能，可以控制 人和囓齒動物類似的神經迴路。這些演化上保守的機制鼓勵 我們利用自閉症小鼠模型，來說明自閉症致病基因如何控制 神經元發育和迴路形成，從而調節社交互動和其他典型的自 閉症相關行為。我們的研究設法了解神經科學領域的關鍵和 基本問題，還將為自閉症的研究提供重要見解。

我們最近的研究可分為四大項：

1. 轉錄因子TBR1 調控左右兩個大腦半球杏仁核之聯結， 以及小鼠類自閉症行為。
2. 神經細胞樹突棘的形成受內質網形成、蛋白質合成和營養的調節。
3. 神經元先天免疫反應調節神經元的形態和功能。
4. 神經元特異性細胞骨架調節劑控制樹突棘的形成和自閉症。

• Education
• Achievements & Honors
• Selected publications
• Lab members

• PDF, 1996-2000, HHMI & Massachusetts General Hospital & Harvard Medical School, USA
• Ph.D., 1995, Graduate Institute of Microbiology & Immunology, National Yang-Ming University
• BS, 1987, Department of Biology, National Taiwan Normal University

• 1986, Tung Di-Gung Award, Ministry of Education (for the student who ranks first at the School of Science, National Taiwan Normal University, Taipei)
• 1991, Scholarship of Chinese Society for Microbiology and Immunology for outstanding graduate student in Immunology.
• 1995, Wang Ming-Ning Award for Medical Ph.D. Thesis.
• 1999, Young Investigator Award, National Neurofibromatosis Foundation, New York, New York.
• 2001, Li Foundation Heritage Prize for Scholarly Development in recognition of research contribution in the field of molecular neurobiology.
• 2005, Academia Sinica Research Award for Young Investigators （年輕學者研究著作獎）
• 2005-2010, 2010-2015, 2015-2020, 2023-2028, Frontier Science Research Grant, National Science and Technology Council or Ministry of Science and Technology (科技部或國科會尖端計畫四次)
• 2008, The 4rd TienTe Lee Award–Young Scientists, TienTe Lee Biomedical Foundation (李天德獎)
• 2016, Explorer Award, Simons Foundation Autism Research Initiative, USA.
• 2017-2022, 2022-2026, Academia Sinica Investigator Award (二次)
• 2019, The 15th TienTe Lee Award–Outstanding, TienTe Lee Biomedical Foundation (李天德獎)
• 2007-2010, 2013-2016, 2016-2019, Distinguished Scholars Research Award, National Science and Technology Council, Ministry of Science and Technology or National Science Council（科技部或國科會傑出研究獎三次）
• 2021 65^th Academic Award of Ministry of Education (教育部學術獎)
• 2022, Merit NSTC Research Fellow, NSTC (國科會傑出特約研究員獎)

1. Hsueh, Y.-P. and Lai, M.-Z.* (1995). JNK but not MAP kinase is sensitive to cAMP inhibition in T Lymphocytes. Journal of Biological Chemistry 270: 18094-18098.
2. Hsueh, Y.-P., Kim, E., and Sheng, M.* (1997). Disulfide-linked head-to-head multimerization in the mechanism of ion channel clustering by PSD-95. Neuron 18: 803-814.
3. Hsueh, Y.-P., Yang, F.-C., Kharazia, V., Naisbitt, S., Cohen, J. M., Weinberg, R. J., and Sheng, M.* (1998). Direct interaction of CASK/LIN-2 and syndecan heparan sulfate proteoglycan and their overlapping distribution in neuronal synapses. Journal of Cell Biology 142:139-151.
4. Hsueh, Y.-P., Wang, T.-F., Yang, F.-C., Sheng M.* (2000) Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2. Nature 404:298-302.
5. Wang, G.-S., Hong, C.-J., Yen, T.-Y., Huang, H.-Y., Ou, Y., Huang, T.-N., Jung, W.-G., Kuo, T.-Y., Sheng, M., Wang, T.-F., and Hsueh, Y.-P.* (2004) Transcriptional Modification by a CASK interacting nucleosome assembly protein. Neuron 42:113-128.
6. Lin, Y.-L., Lei, Y.-T., Hong, C.-J., and Hsueh, Y.-P.* (2007) Syndecan-2 induces filopodia and dendritic spine formation via the neurofibromin-PKA-Ena/VASP pathway. Journal of Cell Biology 177:829-841.
7. Chao, H.-W., Hong, C.-J., Huang, T.-N., Lin, Y.-L., and Hsueh, Y.-P.* (2008) SUMOylation of the MAGUK protein CASK regulates dendritic spinogenesis. Journal of Cell Biology 182:141-155. #Highlighted by Faculty of 1000 Biology
8. Hsueh, Y.-P.* (2009) Calcium/Calmodulin-Dependent Serine Protein Kinase and Mental Retardation. Annals of Neurology 66:438-443.
9. Chen, C.-Y., Lin, C.-W., Chang, C.-Y., Jiang, S.-T., and Hsueh, Y.-P.* (2011) Sarm1, a negative regulator of innate immunity, interacts with syndecan-2 and regulates neuronal morphology. Journal of Cell Biology 193:769-784.
10. #Wang, H.-F., #Shih, Y.-T., #Chen, C.-Y., Chao, H.-W., Lee, M.-J.*, and Hsueh, Y.-P.* (2011) Valosin-containing protein and neurofibromin interact to regulate dendritic spine density. Journal of Clinical Investigation 121:4820-4837. Highlighted by a commentary in the same issue of JCI
11. Huang, T.-N., Chuang, H.-C., Chou, W.-H., Chen, C.-Y., Wang, H.-F., Chou, S.-J., and Hsueh, Y.-P.* (2014) Tbr1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality. Nature Neuroscience 17:240-247.
12. Lee, E.-J., Lee, H., Huang, T.-N., Chung, C., Shin, W., Kim, K., Koh, J.-Y., Hsueh, Y.-P.* and Kim, E.* (2015) Trans-synaptic Zinc mobilization improves social interaction in two mouse models of autism through NMDAR activation. Nature Communications 6:7168.
13. Shih, Y.-T. and Hsueh, Y.-P.* (2016, March) VCP and ATL1 regulate endoplasmic reticulum and control protein synthesis for dendritic spine formation. Nature Communications 7:11020.
14. Chen, C.-Y., Liu, H.-Y., and Hsueh, Y.-P.* (2017) TLR3 downregulates expression of schizophrenia gene Disc1 via MYD88 to control neuronal morphology. EMBO Reports 18:169-183.
15. Hung, Y.-F., Chen, C.-Y., Shih, Y.-C., Liu, H.-Y., Huang, C.-M., and Hsueh, Y.-P.* (Aug, 2018) Endosomal TLR3, TLR7, and TLR8 control neuronal morphology through different transcriptional programs. Journal of Cell Biology 217:2727-2742.
16. Huang, T.-N.#, Hsu, T.-T.#, Hu, H.-T., Chuang, H.-C., Sun, T.-F., Tao, M.-H., Lin, J.Y., and Hsueh, Y.-P.* (2019) Interhemispheric connectivity potentiates the basolateral amygdalae and regulates social interaction and memory. Cell Reports 29:34-48.
17. Shih, P.-Y., Hsieh, B.-Y., Lin, M.-H., Huang, T.-N., Tsai, C.-Y., Pong, W.-L., Lee, S.-P., and Hsueh., Y.-P.* (2020) CTTNBP2 controls synaptic expression of zinc-related autism-associated proteins and regulates synapse formation and autism-like behaviors. Cell Reports 31: 107700.
18. Shih, Y.-T.#, Huang, T.-N.#, Hu, H.-T.#, Yen, T.-L., and Hsueh, Y.-P.* (2020) Vcp overexpression and leucine supplementation increase protein synthesis and improve fear memory and social interaction of Nf1 mutant mice. Cell Reports 31:107835.
19. Shih, P.-Y.#, Fang, Y.-L.#,Shankar, S., Lee, S.-P., Chen, H., Wang, T.-F., Hsia, K.-C.*, Hsueh, Y.-P.* (2022) Phase separation and zinc-induced transition modulate synaptic distribution and association of autism-linked CTTNBP2 and SHANK3. Nature Communications 13:2664 Featured by Nature Communications’ Editor and invited to contribute a blog in “Behind the paper”.
20. Yen, T.-L., Lin, M.-H., Lu, M.-H., Hsu, T.-T., Huang, T.-N. Shih, P.-Y., Ellegood, J., Lerch, J. and Hsueh, Y.-P.* (2023) Sex bias in social deficits, neural circuits and nutrient demand in Cttnbp2 autism models. Brain 146:2612-2626.
21. Hu, H.-T., Lin, Y.-J., Wang, U.-T.T., Lee, S.-P., Liou, Y.-H., Chen, B.-C., and Hsueh, Y.-P.* (2023) Autism-related KLHL17 and SYNPO act in concert to control activity-dependent dendritic spine enlargement and spine apparatus. PLOS Biology 21: e3002274.