不正常的γ-胺基丁酸 (GABA) 神經訊息傳遞與許多腦部疾病相關，最常見的疾病包括癲癇、自閉症、思覺失調症與情感障礙等。哺乳類動物腦中的GABA中間神經元擁有多樣化的特性，這樣的特性卻使得研究者卻步，因為這意味著若想要全然地瞭解腦功能，必定要先清楚研究各種中間神經元的分子與細胞層級活動。過去十年間，本實驗室的研究專注於瞭解神經系統中GABA中間神經元的多樣性功能，其中我與我的同事們發現且仔細研究「不同亞型的GABA中間神經元其不同的特殊性質與功能」，這些研究成果對於正處於快速發展階段的中間神經元多樣性研究具有重要的貢獻。首先我們指出在高頻動作電位中間神經元中，無失活性電位控制型鉀離子通道Kv3亞型能在動力學上調節高頻率動作電位的產生 (發表於Lien et al., J Physiology, 2002; Lien and Jonas, J Neuroscience, 2003)。另外，我們發現在海馬中間神經元中，大麻素神經傳遞訊息可使電位控制型鉀離子通道Kv3亞型快速失活 (發表於Oliver*, Lien* et al., 2004; Science; *equal contribution)。除此之外，根據我們的研究結果得知，在一類特定的GABA突觸中，突觸前的N-甲基-D-天門冬胺酸 (NMDA) 受體能促使突觸後訊號產生長期抑制作用 (發表於Lien et al., Nature Neuroscience, 2006)。
近五年，本實驗室的研究專注於瞭解神經系統中GABA神經元的多樣性功能。我們發現抑制性神經傳遞質GABA在成熟的齒狀迴中具有分流式抑制效果(shunting inhibition)，且依據GABA神經活動精確的發生時間與地點，GABA在突觸訊號整合過程中時而扮演抑制性角色、又時而扮演興奮性角色 (Chiang et al., J Neuroscience, 2012; Rank: top 10% in NEUROSCIENCES)。最近，我們研究發現海馬齒狀迴中的細胞體投射型與樹突投射型GABA神經元具有完全相異卻互補的突觸功能，此發現證實皮質神經網絡中獨特的神經訊號計算功能可經由不同亞型的中間神經元執行，也就是各類中間神經元具有各自分工並影響訊息傳遞的特性 (發表於Liu et al., J Neuroscience, 2014; Rank: top 10% in NEUROSCIENCES)。
最近我們發展光遺傳學(optogenetics)技術，此技術是把對特定光波敏感的離子通道或離子運輸蛋白利用遺傳學的方法表現在特定神經細胞的細胞膜上面，以特定光源來開啟光波敏感的離子通道或離子運輸蛋白，進而達到激發或抑制此一特定神經細胞，進而探討神經迴路與行為之相關性。我們最近結合電生理與光遺傳學試圖去定位海馬齒狀回內的抑制性迴路是否受特定外來興奮性路徑的活化。根據初步的研究結果，我們發現不同類的齒狀迴GABA神經元會被不同的興奮性神經輸入路徑所活化。總結來說，我們發現若是不同群體的齒狀迴GABA神經元被不同興奮性路徑活化，代表各類GABA神經元在齒狀迴訊息運算中提供不盡相同的功能。在此計畫中，我們將主要研究中穿路徑與聯合路徑對各類抑制神經元的影響與調控，研究成果即將發表在Cerebral Cortex (Hsu et al., 2015; Rank: top 10% in NEUROSCIENCES)。
總結來說，我過去近五年的研究成果已為GABA神經元的多樣性功能研究寫下重要的一頁。此一系列的研究成果已受到國際社會的肯定，Gordon Research Conference (GRC) 主辦單位於今年八月主辦2015 inhibition in the CNS 的會議邀請我就《抑制性突觸與迴路Inhibitory Synapses and Circuits》主題給一場演講，我目前也擔任Frontiers in Cellular Neuroscience (SCI 4.2), Scientific Reports (SCI 5.57), Matters (new journal) 的Review Editorial Board Members。
2.酸敏感性離子通道與恐懼記憶的研究
酸敏感性離子通道與哺乳類動物的學習和記憶有關。此基因的單核苷酸多態性(Single Nucleotide Polymorphism，簡稱SNP)與人類的恐慌症有高度相關性。早期的研究認為酸敏感性離子通道基因剔除鼠有空間記憶與恐懼學習的缺陷，但從分子與細胞以至於網路的機制都不甚清楚。於2010年我們第一個利用高解析度單細胞基因分析與單細胞離子通道功能紀錄，報導酸敏感性離子通道於海馬迴神經網路的基因與功能性表現。我們發現不同類型的GABA神經元具有相異極大的酸敏感性離子通道表現，並且其門控特性與組成亞型也十分不同。因為酸敏感性通道的缺失與癲癇有密切相關，我們推斷酸敏感性離子通道於不同類型之GABA神經元的表現極有可能與不同GABA神經元在正常與異常神經網絡中的功能與貢獻度有所關聯(Weng et al., J Neuroscience, 2010; Rank: top 10% in NEUROSCIENCES)。此篇研究隨即於隔年被Nature protocol (Citri et al., 2011)給引用。為了探討此特定基因缺失所造成的功能性改變，我們與台大基因轉殖鼠核心實驗室合作生產了酸敏感性離子通道的條件式基因剔除鼠。我們發現，酸敏感性離子通道基因剔除鼠的恐懼學習(情境式恐懼記憶與線索制約誘發恐懼記憶)有明顯缺陷，但是空間記憶卻是正常的，進一步我們發現酸敏感性離子通道基因剔除鼠的海馬迴長期突觸可塑性是正常的。我們的發現推翻了過去長期認為酸敏感性離子通道在空間記憶與突觸可塑性中扮演必要角色 (J Neurosci; Wu et al., 2013; Rank: top 10% in NEUROSCIENCES)。我們將此一系列的研究成果陸續發表了兩篇研究論文在神經科學領域內排名Top 8%的論文Journal of Neuroscience。
Wu PC, Fann MJ, Tran TT, Chen SC, Devina T, Cheng IH, Lien CC, Kao LS, Wang SJ, Fuh JL, Tzeng TT, Huang CY, Shiao YJ, Wong YH. Assessing the therapeutic potential of Graptopetalum paraguayense on Alzheimer's disease using patient iPSC-derived neurons. Sci Rep. 2019 Dec 17;9(1):19301. doi: 10.1038/s41598-019-55614-9. [PDF][PubMed]
2.
Hsu YT, Chang YG, Liu YC, Wang KY, Chen HM, Lee DJ, Yang SS, Tsai CH, Lien CC, Chern YJ. Enhanced Na+-K+-2Cl- cotransporter 1 underlies motor dysfunction in Huntington's disease. Mov Disord. 2019 Mar 6. [Epub ahead of print]. (Co-corresponding author) [PDF][PubMed]
論文&書籍
1.
Wu PC, Fann MJ, Tran TT, Chen SC, Devina T, Cheng IH, Lien CC, Kao LS, Wang SJ, Fuh JL, Tzeng TT, Huang CY, Shiao YJ, Wong YH. Assessing the therapeutic potential of Graptopetalum paraguayense on Alzheimer's disease using patient iPSC-derived neurons. Sci Rep. 2019 Dec 17;9(1):19301. doi: 10.1038/s41598-019-55614-9. [PDF][PubMed]
2.
Hsu YT, Chang YG, Liu YC, Wang KY, Chen HM, Lee DJ, Yang SS, Tsai CH, Lien CC, Chern YJ. Enhanced Na+-K+-2Cl- cotransporter 1 underlies motor dysfunction in Huntington's disease. Mov Disord. 2019 Mar 6. [Epub ahead of print]. (Co-corresponding author) [PDF][PubMed]
3.
Chen CY, Di Lucente J, Lin YC, Lien CC, Rogawski MA, Maezawa I, Jin LW. Defective GABAergic neurotransmission in the nucleus tractus solitarius in Mecp2-null mice, a model of Rett syndrome. Neurobiol Dis 2018 Jan; 109(Pt A): 25-32. [PDF][PubMed]
4.
Martina M., Lien CC. (2018) Physiological Properties of Hippocampal Neurons. In: Cutsuridis V., Graham B., Cobb S., Vida I. (eds) Hippocampal Microcircuits. Springer Series in Computational Neuroscience. Springer, Cham. (co-corresponding author) [PDF][Link]
5.
Huang CY, Lien CC, Cheng CF, Yen TY, Chen CJ, Tsaur ML. K+ channel Kv3.4 is essential for axon growth by limiting the influx of Ca2+ into growth cones. J Neurosci 2017 April; 37(17): 4433-4449. [PDF][PubMed]
6.
Kuo YL, Cheng JK, Hou WH, Chang YC, Du PH, Jian JJ, Rau RH, Yang JH, Lien CC, Tsaur ML. K+ channel modulatory subunits KChIP and DPP participate in Kv4-mediated mechanical pain control. J Neurosci 2017 April; 37(16): 4391-4404. [PDF][PubMed]
7.
Lee CT, Kao MH, Hou WH, Wei YT, Chen CL, Lien CC. Causal evidence for the role of specific GABAergic interneuron types in entorhinal recruitment of dentate granule cells. Sci Rep 2016 Nov; 6: 36885. (Corresponding author) [PDF][PubMed][Supplementary Information]
8.
Wu CC, Lien CC, Hou WH, Chiang PM, Tsai KJ. Gain of BDNF function in engrafted neural stem cells promotes the therapeutic potential for Alzheimer's disease. Sci Rep 2016 Jun; 6: 27358. [PDF][PubMed]
9.
Hsu TT, Lee CT, Tai MH, Lien CC. Differential recruitment of dentate gyrus interneuron types by commissural versus perforant pathways. Cereb Cortex 2016 Jun; 26(6): 2715-27. (Corresponding author) [PDF][Supporting information][PebMed]
10.
Hou WH, Kuo N, Fang GW, Huang HS, Wu KP, Zimmer A, Cheng JK, Lien CC. Wiring Specificity and Synaptic Diversity in the Mouse Lateral Central Amygdala. J Neurosci 2016 April; 36(16): 4549-4563. (Corresponding author) (Featured Article)[PDF][PubMed]; also see Editor's Commentary [PDF][PDF (Chinese Ver.)]
11.
Chang CP, Lee CT, Hou WH, Lin MS, Lai HL, Chien CL, Chang C, Cheng PL, Lien CC*, Chern Y. Type VI adenylyl cyclase negatively regulates GluN2B-mediated LTD and spatial reversal learning. Sci Rep 2016 Mar; 6(22529): 1-16. (*co-corresponding author) [PDF][Supporting information][PebMed]
12.
Chiang PH, Chien TC, Chen CC, Yanagawa Y, Lien CC. ASIC-dependent LTP at multiple glutamatergic synapses in amygdala network is required for fear memory. Sci Rep 2015 May 19; 5: 10143. (Corresponding author) [PDF][Supporting information][PubMed]
13.
Lin SH, Chien YC, Chiang WW, Liu YZ, Lien CC, Chen CC.Genetic mapping of ASIC4 and contrasting phenotype to ASIC1a in modulating innate fear and anxiety. Eur J Neurosci 2015 Jun; 41(12): 1553-68.[PDF][PebMed]
14.
Chen WT, Hsieh YF, Huang YJ, Lin CC, Lin YT, Liu YC, Lien CC, Cheng IH. G206D mutation of Presenilin-1 reduces Pen2 interaction, increases Aβ42/Aβ40 ratio and elevates ER Ca2+ accumulation. Mol Neurobiol 2015 Dec; 52(3): 1835-49.[PebMed]
15.
Cheng CF, Cheng JK, Chen CY, Lien CC, Chu D, Wang SY, Tsaur ML. Mirror-image pain is mediated by NGF produced from TNFactivated satellite glia after peripheral nerve injury. Pain 2014 May; 155(5): 906-20.[PDF][Supporting information][PebMed]
16.
Liu YC, Cheng JK, Lien CC. Rapid dynamic changes of dendritic inhibition in the dentate gyrus by presynaptic activity patterns. J Neurosci 2014 Jan 22; 34(4): 1344-1357. (Corresponding author)[PDF][PebMed]
17.
Chan CF*, Kuo TW*, Weng JY*, Lin YC*, Chen TY*, Cheng JK, Lien CC. Ba2+- and bupivacaine-sensitive background K+ conductances mediate rapid EPSP attenuation in oligodendrocyte precursor cells. J Physiol (London) 2013 Oct 1; 591(19): 4843-58. *Co-First author (Corresponding author)[PDF][PebMed]
18.
Sun YY, Lin SH, Lin HC, Hung CC, Wang CY, Lin YC, Hung KS, Lien CC, Kuan CY, Lee YH. Cell type-specific denpendency on the PI3K/Akt signaling pathway for the endogenous Epo and VEGF induction by baicalein in neurons versus astrocytes. PLoS ONE 2013 Jul 9; 8(7): e69019. [PDF][Supporting information][PebMed]
19.
Wu PY, Huang YY, Chen CC, Hsu TT, Lin YC, Weng JY, Chien TC, Cheng H, Lien CC. Acid-sensing ion channel-1a is not required for normal hippocampal LTP and spatial memory. J Neurosci 2013 Jan; 33 (5): 1828-32. (Corresponding author) [PDF][PebMed]
20.
Lee YC, Alexandra D, Majczenko K, Huang YH,Liu YC, Lien CC, Tsai PC, Ichikawa Y, Goto J, Monin ML, Li JZ, Chung MY, Mundwiller E, Shakkottai V, Liu TT, Tesson C, Lu YC, Brice A, Tsuji S, Burmeister M, Stevanin G, Soong BW. Mutations in KCND3 cause spinocerebellar ataxia type 22. Ann Neurol 2012 Dec; 72 (6): 859-69.[PDF][Supporting Information][PebMed]
Chiang PH*, Wu PY*, Kuo TW*, Liu YC, Chan CF, Chien TC, Cheng JK, Huang YY, Chiu CD, Lien CC. GABA is depolarizing in hippocampal dentate granule cells of the adolescent and adult rats. J Neurosci 2012 Jan 4;32: 62-67. *Co-First author (Corresponding author)[PDF][PebMed]
23.
Lin YC, Liu YC, Huang YY, Lien CC. High-density expression of Ca2+-permeable ASIC1a channels in NG2 glia of rat hippocampus. PLoS ONE 2010 Sep 10; 5 (9): e12665-e12672. (Corresponding author)[PDF][PebMed]
24.
Chu KC, Chiu CD, Hsu TT, Hsieh YM, Huang YY, Lien CC. Functional identification of an outwardly rectifying pH- and anesthetic-sensitive leak K+ conductance in hippocampal astrocytes. Eur J Neurosci 2010 Jul 28; 32: 725-35. (Corresponding author)[PDF][Supporting Information][PebMed]
25.
Weng JY, Lin YC, Lien CC. Cell type-specific expression of acid-sensing ion channels in hippocampal interneurons. J Neurosci 2010 May 12; 30: 6548-58. (Corresponding author)[PDF][Supplementary Information][PebMed]
26.
Chiang PH, Yeh WC, Lee CT, Weng JY, Huang YY, Lien CC. M1-like muscarinic acetylcholine receptors regulate fast-spiking interneuron excitability in rat dentate gyrus. Neuroscience 2010 Aug 11; 169: 39-51. Epub 2010 Apr 28. (Corresponding author)[PDF][PebMed]
27.
Liao CW & Lien CC. Estimating intracellular Ca2+ concentrations and buffering in a dendritic inhibitory hippocampal interneuron. Neuroscience 2009 Dec 4; 164: 1701-11. (Corresponding author)[PDF][PebMed]
28.
Aponte Y, Lien CC, Jonas P. Hyperpolarization-activated cation channels in fast-spiking hippocampal interneurons. J Physiol (London) 2006 Jul 1; 574: 229-43.[PDF][PebMed]
29.
Lien CC, Mu Y, Vargas-Caballero M, Poo MM. Visual stimuli-induced LTD of GABAergic synapses mediated by presynaptic NMDA receptors. Nat Neurosci 2006 Mar; 9: 372-80.[PDF][Supplementary Information][PebMed]
30.
Oliver D*, Lien CC*, Soom M, Baukrowitz T, Jonas P, Fakler B. Functional conversion between A-type and delayed rectifier K+ channels by membrane lipids. Science (Research Article) 2004 Apr 9; 304: 265-70. (*equal contribution)[PDF][Supporting Online Material][PebMed]
31.
Lien CC & Jonas P. Kv3 potassium conductance is necessary and kinetically optimized for high-frequency action potential generation in hippocampal interneurons. J Neurosci 2003 Mar 15; 23: 2058-68.[PDF][PebMed]
32.
Lien CC, Martina M, Schultz J, Ehmke H, Jonas P. Gating, modulation, and subunit composition of voltage-gated K+ channels in dendritic inhibitory interneurones of rat hippocampus. J Physiol (London) 2002 Jan 15; 538: 405-19.[PDF][PebMed]
