相關閱讀資料
細胞與分子神經生物學：腦與認知科學III
因舊版課程無指定課堂作業與考試，因此統整所有作業、講義、考試內容合併列出。
細胞與分子神經生物學：腦與認知科學III
因舊版課程無指定課堂作業與考試，因此統整所有作業、講義、考試內容合併列出。
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下列閱讀資料是這門課的基礎。點擊鏈接可查看學報文章的摘要。 The readings listed below provide the foundation of this course. Click on the links to view abstracts for the journal articles, where available.
學生簡報 Student Presentations 學生可從以下題目中選擇一個，並閱讀其列出的閱讀資料，為課堂簡報作準備。
Students choose from the following topics, and read the articles listed for that topic, in preparation for their class presentations.
鉀通道 Choe. "Potassium Channel Structures," Nat Rev Neurosci. 2002 Feb;3(2):115 [background and review]. PubMed摘要：K+通道功能的分子基礎是普遍地發揮保護作用的。K+通道可讓K+流動，對透過應激的隔膜來產生電流很重要。K+ 通道還是各種細胞內部控制機制的作用物件，因此不良的通道功能調節可能與致病的原因有關。由於K+通道在控制隔膜興奮性上有重要作用，因此系統地瞭解它們的功能和調節，將為瞭解神經生理學提供有用的框架。很多新近的生理學和晶體研究，都讓我們對K+通道的作用有新的認識。
PubMed abstract: The molecular basis of K+ channel function is universally conserved. K+ channels allow K+ flux and are essential for the generation of electric current across excitable membranes. K+ channels are also the targets of various intracellular control mechanisms, such that the suboptimal regulation of channel function might be related to pathological conditions. Because of the fundamental role of K+ channels in controlling membrane excitability, a structural understanding of their function and regulation will provide a useful framework for understanding neuronal physiology. Many recent physiological and crystallographic studies have led to new insights into the workings of K+ channels. Doyle等.〈鉀通道的結構: K+傳導和選擇性的分子基礎〉，《科學》. 1998 Apr 3;280(5360):69-77 [基礎文章]. Doyle, et al. "The Structure of the Potassium Channel: Molecular Basis of K+ Conduction and Selectivity," Science. 1998 Apr 3;280(5360):69-77 [primary article]. PubMed摘要：變鉛青鏈黴菌中的鉀通道是一個整體的膜蛋白，序列與大家熟悉的K+通道相似，特別是細孔部分。帶3.2埃資料的X射線分析顯示，四個相同的亞單元形成一個倒圓錐或錐型，在外端生成細孔的選擇性篩檢程式。狹窄的選擇性篩檢程式只有12埃長，但細孔的多出部分較寬並伴有疏水性氨基酸。通過放置大的充水腔和螺旋偶極子，可抵禦雙分子層中心細孔離子的靜電干擾。K+通道信號序列中主要的鏈羰基氧原子沿選擇性篩檢程式排列，由於結構上的限制，篩檢程式向相應的K＋離子開放，而排斥較小的Na+離子。選擇性篩檢程式包含兩個相距7.5的K+離子。這樣的結構通過利用靜電斥力來消弭K+離子和篩檢程式之間的引力，從而達到離子傳導。細孔的構造形成了基本選擇性K+傳導的物理基礎。
PubMed abstract: The potassium channel from Streptomyces lividans is an integral membrane protein with sequence similarity to all known K+ channels, particularly in the pore region. X-ray analysis with data to 3.2 angstroms reveals that four identical subunits create an inverted teepee, or cone, cradling the selectivity filter of the pore in its outer end. The narrow selectivity filter is only 12 angstroms long, whereas the remainder of the pore is wider and lined with hydrophobic amino acids. A large water-filled cavity and helix dipoles are positioned so as to overcome electrostatic destabilization of an ion in the pore at the center of the bilayer. Main chain carbonyl oxygen atoms from the K+ channel signature sequence line the selectivity filter, which is held open by structural constraints to coordinate K+ ions but not smaller Na+ ions. The selectivity filter contains two K+ ions about 7.5 angstroms apart. This configuration promotes ion conduction by exploiting electrostatic repulsive forces to overcome attractive forces between K+ ions and the selectivity filter. The architecture of the pore establishes the physical principles underlying selective K+ conduction. He等. 〈鴉片受體運行的調節和受體低聚化的嗎啡容受量〉,《細胞》. 2002 Jan 25;108(2):271-82 [基礎文章]. He, et al. "Regulation of Opioid Receptor Trafficking and Morphine Tolerance by Receptor Oligomerization," Cell. 2002 Jan 25;108(2):271-82 [primary article]. PubMed摘要：藥物鎮痛作用中耐藥性的發展，阻礙了長期痛症治療中嗎啡的使用。在鎮靜劑中，嗎啡有啟動mu鴉片受體(MOR)的獨體功效，同時不會產生脫敏和內噬作用。在此，我們證明了[D-Ala(2)-MePhe(4)-Gly(5)-ol]腦啡肽(DAMGO)可以促進嗎啡的作用，激發MOR內噬作用。這樣，長期使用兩種藥物的老鼠相較於只用嗎啡的老鼠，前者對止痛劑的耐藥性更低。這些結果證明，MOR的內噬作用可以減緩耐藥性的發展，因此提出了鎮靜類藥物的發展方法，同時改善長期痛症的治療效力。
PubMed abstract: The utility of morphine for the treatment of chronic pain is hindered by the development of tolerance to the analgesic effects of the drug. Morphine is unique among opiates in its ability to activate the mu opioid receptor (MOR) without promoting its desensitization and endocytosis. Here we demonstrate that [D-Ala(2)-MePhe(4)-Gly(5)-ol] enkephalin (DAMGO) can facilitate the ability of morphine to stimulate MOR endocytosis. As a consequence, rats treated chronically with both drugs show reduced analgesic tolerance compared to rats treated with morphine alone. These results demonstrate that endocytosis of the MOR can reduce the development of tolerance, and hence suggest an approach for the development of opiate analogs with enhanced efficacy for the treatment of chronic pain. Pierce等.〈七橫跨膜受體〉，《國家分子細胞生物評論》. 2002 Sep;3(9):639-50 [背景和評論]. Pierce, et al. "Seven-Transmembrane Receptors," Nat Rev Mol Cell Biol. 2002 Sep;3(9):639-50 [background and review]. PubMed摘要：七跨膜受體組成了最大、最普遍和最多樣的膜受體族，也是治療藥物最經常的目標。最近的研究發現指出，G蛋白耦合的古典模型和第二信使生成酶的活化，不能充分解釋它們顯著不同的生物作用。
PubMed abstract: Seven-transmembrane receptors, which constitute the largest, most ubiquitous and most versatile family of membrane receptors, are also the most common target of therapeutic drugs. Recent findings indicate that the classical models of G-protein coupling and activation of second-messenger-generating enzymes do not fully explain their remarkably diverse biological actions. 神經誘導 Piccolo等.〈爪蟾的背腹結構:通過脊索蛋白直接結合到BMP-4以阻止腹部信號〉，《細胞》. 1996 Aug 23;86(4):589-98. Piccolo, et al. "Dorsoventral Patterning in Xenopus: Inhibition of Ventral Signals by Direct Binding of Chordin to BMP-4." Cell. 1996 Aug 23;86(4):589-98. PubMed摘要：Chordin (Chd)是原腸胚形成中，施佩曼組織器結構分泌的一種豐富蛋白質。Chd通過阻斷與成熟骨形態形成蛋白（BMPs）受體的結合，拮抗BMP發出的信號。重組爪蟾Chd與BMP-4緊密結合(KD, 3 x 10(-10) M)，特定地與BMP相連，而不是與活化素或TGF-beta1相連。Chd蛋白質可以使中胚葉背部化，也可以背化1海哩的爪蟾腸胚外植體裏面的外胚層。我們提出，施佩曼組織器對背腹式的非細胞自發功能，有部分是通過原腸胚形成過程中，直接結合和抵消腹部BMP的擴散性信號所發揮的。
PubMed abstract: Chordin (Chd) is an abundant protein secreted by Spemann organizer tissue during gastrulation. Chd antagonizes signaling by mature bone morphogenetic proteins (BMPs) by blocking binding to their receptors. Recombinant Xenopus Chd binds to BMP-4 with high affinity (KD, 3 x 10(-10) M), binding specifically to BMPs but not to activin or TGF-beta1. Chd protein is able to dorsalize mesoderm and to neuralize ectoderm in Xenopus gastrula explants at 1 nM. We propose that the noncell-autonomous effects of Spemann's organizer on dorsoventral patterning are executed in part by diffusible signals that directly bind to and neutralize ventral BMPs during gastrulation. 區域化 Houart等.〈因WNT信號局部對抗而產生的原腸胚形成過程中，前腦胞的形成〉，《神經元》. 2002 Jul 18;35(2):255-65. Houart, et al. "Establishment of the Telencephalon during Gastrulation by Local Antagonism of Wnt Signaling." Neuron. 2002 Jul 18;35(2):255-65. 神經形成和移動 PubMed摘要：神經板前部的細胞（ANB）可以在轉移到靠後部區域時，引起前腦胞基因表達。我們在辨識出了一種分泌型捲曲相關的Wnt拮抗物Tlc，它在ANB細胞中表達，並以濃度依賴形態，非自發地促進前腦胞基因表達。而且，Tlc功能的消除對前腦胞的發展不利。我們還辨識出Wnt8b是神經板前部區域活動的局部作用調節器，也很可能是Tlc拮抗的靶標。最後，我們表明，tlc表達是由信號來調控的，它建立了早期前後和腹背外胚層模式。根據這些研究，我們提出，Wnt在前外胚層活動的局部拮抗對建立前腦胞來說是必要的。
PubMed abstract: Cells at the anterior boundary of the neural plate (ANB) can induce telencephalic gene expression when transplanted to more posterior regions. Here, we identify a secreted Frizzled-related Wnt antagonist, Tlc, that is expressed in ANB cells and can cell nonautonomously promote telencephalic gene expression in a concentration-dependent manner. Moreover, abrogation of Tlc function compromises telencephalic development. We also identify Wnt8b as a locally acting modulator of regional fate in the anterior neural plate and a likely target for antagonism by Tlc. Finally, we show that tlc expression is regulated by signals that establish early antero-posterior and dorso-ventral ectodermal pattern. From these studies, we propose that local antagonism of Wnt activity within the anterior ectoderm is required to establish the telencephalon. Wu等.〈在嗅覺系統中,蛋白裂引起神經元移動的方向性導向〉,《自然》. 1999 Jul 22;400(6742):331-6. Wu, et al. "Directional guidance of neuronal migration in the olfactory system by the protein Slit." Nature. 1999 Jul 22;400(6742):331-6. PubMed摘要：雖然細胞移動對神經發展很重要，但我們對分子機制導控的神經元移動還是不清楚。在此，我們講述分泌蛋白裂將自前腦胞室管膜前下區移出的神經元前體細胞，排斥到嗅球。我們的研究結果直接證明了，分子因數的濃度梯度引導神經元的移動方向。這樣的結果，還支持了軸突發射和神經元移動的普通導向機制，並提出蛋白裂可以提供分子工具，這在控制和引導細胞遷移上都有潛在的治療實用性。
PubMed abstract: Although cell migration is crucial for neural development, molecular mechanisms guiding neuronal migration have remained unclear. Here we report that the secreted protein Slit repels neuronal precursors migrating from the anterior subventricular zone in the telencephalon to the olfactory bulb. Our results provide a direct demonstration of a molecular cue whose concentration gradient guides the direction of migrating neurons. They also support a common guidance mechanism for axon projection and neuronal migration and suggest that Slit may provide a molecular tool with potential therapeutic applications in controlling and directing cell migration. 神經元細胞生物學，亞細胞特化性 Hering和Sheng. 〈樹枝狀脊骨：結構、動力學和規則〉，《國家神經科學評論》. 2001 Dec;2(12):880-8. [背景和評論]. Hering and Sheng. "Dendritic spines: structure, dynamics and regulation." Nat Rev Neurosci. 2001 Dec;2(12):880-8. [Background and Review]. Shi等.〈經由mPar3/mPar6的空間局部化和PI 3－激酶活性局部化以確定的海馬趾神經元極性〉，《細胞》. 2003 Jan 10;112(1):63-75. [基礎文章]. Shi, et al. "Hippocampal Neuronal Polarity Specified by Spatially Localized mPar3/mPar6 and PI 3-Kinase Activity." Cell. 2003 Jan 10;112(1):63-75. [Primary Article]. PubMed摘要：神經元如何極化還是一個顯著的問題。在此，我們講述了在培育的海馬趾神經元中，選擇未來軸突需要生長因數受體酪氨酸激酶，磷脂醯肌醇3激酶(PI 3-kinase)，還有非典型蛋白激酶C(aPKC)。磷脂醯肌醇3激酶的活動高度停留在第三階段神經元新近確定的軸突邊沿，該激酶對mPar3適當的亞細胞定位——線蟲的哺乳類極蛋白Par3很重要。不僅是mPar3 ，mPar6的極化分佈對軸突形成來說都是很重要的；mPar6、mPar3或mPar3N端的異常表達都會對神經元出現不確定軸突的情況。因此，神經元的極性很可能被mPar3/mPar6/aPKC複合體和磷脂醯肌醇3激酶信號路徑控制，這兩者都在確定細胞極性上都有著進化的保存作用。
PubMed abstract: How a neuron becomes polarized remains an outstanding question. Here, we report that selection of the future axon among neurites of a cultured hippocampal neuron requires the activity of growth factor receptor tyrosine kinase, phosphatidylinositol 3-kinase (PI 3-kinase), as well as atypical protein kinase C (aPKC). The PI 3-kinase activity, highly localized to the tip of the newly specified axon of stage 3 neurons, is essential for the proper subcellular localization of mPar3, the mammalian homolog of C. elegans polarity protein Par3. Polarized distribution of not only mPar3 but also mPar6 is important for axon formation; ectopic expression of mPar6 or mPar3, or just the N terminus of mPar3, leaves neurons with no axon specified. Thus, neuronal polarity is likely to be controlled by the mPar3/mPar6/aPKC complex and the PI 3-kinase signaling pathway, both serving evolutionarily conserved roles in specifying cell polarity. 蛋白質定位，信號複合體 Sheng和Sala.〈PDZ域和超分子複合體組織〉，《神經科學評論年鑒》. 2001;24:1-29. [背景和評論] Sheng and Sala. "PDZ domains and the organization of supramolecular complexes." Annu Rev Neurosci. 2001;24:1-29. [Background and Review]. PubMed摘要：PDZ域是模蛋白相互作用域，與短C末端縮氨酸或內縮氨酸以特定順序方式結合，折合在beta指中。PDZ結合特異性的多樣化，可以通過PDZ域縮氨酸結合槽的可變氨基酸來解釋。在秀麗線蟲、黑腹果蠅和哺乳染色體組裏充分顯示出PDZ域的作用，PDZ域經常在多複製體裏出現，或者在多域支架蛋白裏和其他蛋白質結合的家族模體結合。含PDZ的蛋白質經常在超分子複合體組合中存在，在特定的亞細胞區域發揮定位信號的功能。根據基於PDZ支架的組織可以穩定相互作用蛋白質的定位，提高複合體內信號轉換的速度和可靠性。一些含有PDZ的蛋白質在分佈上更能動態調節，或許還可以在細胞內相互作用的蛋白質傳輸中發揮作用。
PubMed abstract: PDZ domains are modular protein interaction domains that bind in a sequence-specific fashion to short C-terminal peptides or internal peptides that fold in a beta-finger. The diversity of PDZ binding specificities can be explained by variable amino acids lining the peptide-binding groove of the PDZ domain. Abundantly represented in Caenorhabditis elegans, Drosophila melanogaster, and mammalian genomes, PDZ domains are frequently found in multiple copies or are associated with other protein-binding motifs in multidomain scaffold proteins. PDZ-containing proteins are typically involved in the assembly of supramolecular complexes that perform localized signaling functions at particular subcellular locations. Organization around a PDZ-based scaffold allows the stable localization of interacting proteins and enhances the rate and fidelity of signal transduction within the complex. Some PDZ-containing proteins are more dynamically regulated in distribution and may also be involved in the trafficking of interacting proteins within the cell. Tsunoda等.〈在G蛋白連結噴流下的多價PDZ域蛋白聚集信號複合物〉，《自然》. 1997 Jul 17;388(6639):243-9.[基礎文章]. Tsunoda, et al. "A multivalent PDZ-domain protein assembles signalling complexes in a G-protein-coupled cascade." Nature. 1997 Jul 17;388(6639):243-9.[Primary Article]. PubMed摘要：同一細胞內信號分子如何安排進入不同路徑？在果蠅中，naD基因編碼的蛋白質由5個PDZ域組成，作為支架合成光傳導串連的不同部分，包括光啟動的主要離子通道、受動器磷脂酶C-beta和蛋白激酶C。無效inaD突變異種有戲劇性重組的亞細胞信號分子分佈，徹底失去轉換複合體。還有，單個PDZ域中突變異種缺陷產生信號複合體，缺乏目的蛋白並在這些複合體的生理上有相應缺陷。高度組織的信號單位「轉換組（transduclisome）」，含PDZ域機能，作為活體轉換複合體組織的重要成分。
PubMed abstract: How are signalling molecules organized into different pathways within the same cell? In Drosophila, the inaD gene encodes a protein consisting of five PDZ domains which serves as a scaffold to assemble different components of the phototransduction cascade, including the principal light-activated ion channels, the effector phospholipase C-beta and protein kinase C. Null inaD mutants have a dramatically reorganized subcellular distribution of signalling molecules, and a total loss of transduction complexes. Also, mutants defective in a single PDZ domain produce signalling complexes that lack the target protein and display corresponding defects in their physiology. A picture emerges of a highly organized unit of signalling, a 'transduclisome', with PDZ domains functioning as key elements in the organization of transduction complexes in vivo. 神經元的決定和分化 Wichterle等.〈胚胎幹細胞到運動神經元的定向分化〉，《細胞》. 2002 Aug 9;110(3):385-97. Wichterle, et al. "Directed Differentiation of Embryonic Stem Cells into Motor Neurons." Cell. 2002 Aug 9;110(3):385-97. PubMed摘要：運動神經元生成中起作用的引導信號和轉錄遺傳因子已經被確知，並引起了這些發展觀點可否用於引導幹細胞進入運動神經元活動的問題。我們講述了發展相關信號遺傳因子，可以引導大鼠胚胎幹(ES)細胞先在脊髓源細胞中細分，接著通過活體中使用的通道進入動力神經元。ES細胞所產生的動力神經元可以承載胚胎脊索、延伸突觸、以及形成帶目的肌的突觸。所以，在正常神經形成通道中起作用的引導信號，可以引導ES細胞形成特定的CNS神經元族類。
PubMed abstract: Inductive signals and transcription factors involved in motor neuron generation have been identified, raising the question of whether these developmental insights can be used to direct stem cells to a motor neuron fate. We show that developmentally relevant signaling factors can induce mouse embryonic stem (ES) cells to differentiate into spinal progenitor cells, and subsequently into motor neurons, through a pathway recapitulating that used in vivo. ES cell-derived motor neurons can populate the embryonic spinal cord, extend axons, and form synapses with target muscles. Thus, inductive signals involved in normal pathways of neurogenesis can direct ES cells to form specific classes of CNS neurons. 軸突導向I：生長錐能動性；因子和受體 Stein和Tessier-Lavigne.〈導向受體的等級組織：通過裂透Robo/DDC受體複合物以衍生對神經突起生長導向因子吸引的抑制〉，《科學》. 2001 Mar 9;291(5510):1928-38. Epub 2001 Feb 08. Stein and Tessier-Lavigne. "Hierarchical Organization of Guidance Receptors: Silencing of Netrin Attraction by Slit Through a Robo/DCC Receptor Complex." Science. 2001 Mar 9;291(5510):1928-38. Epub 2001 Feb 08. PubMed摘要：通過神經系統中線的突觸生長圓錐細胞，改變它們對中線導向信號的反應：它們被排斥分裂所排斥，同時失去對軸突導向因子netrin的回應。通過把曾經吸引的環境變成排斥，這些相輔相成的改變把生長圓錐細胞從中線裏驅除出來。在此，我們證明這兩個改變是因果相連的：在爪蟾胚胎脊髓突觸的生長細胞中，分裂受體Roundabout(Robo)的活化抑制軸突導向因子netrin-1的吸引作用，而非它的生長促進作用，這是通過直接結合Robo和netrin受體DDC的細胞質域實現的。在生物學上，這個層級的抑制機制，可以在生長圓錐細胞中阻止吸引和排斥信號的衝突，避免產生混亂。從分子上看，通過這些潛在拮抗受體細胞質域的模組和聯鎖設計，形成了抑制，而這些受體可以預先確定同時出現之活化作用的影響。
PubMed abstract: Axonal growth cones that cross the nervous system midline change their responsiveness to midline guidance cues: They become repelled by the repellent Slit and simultaneously lose responsiveness to the attractant netrin. These mutually reinforcing changes help to expel growth cones from the midline by making a once-attractive environment appear repulsive. Here, we provide evidence that these two changes are causally linked: In the growth cones of embryonic Xenopus spinal axons, activation of the Slit receptor Roundabout (Robo) silences the attractive effect of netrin-1, but not its growth-stimulatory effect, through direct binding of the cytoplasmic domain of Robo to that of the netrin receptor DCC. Biologically, this hierarchical silencing mechanism helps to prevent a tug-of-war between attractive and repulsive signals in the growth cone that might cause confusion. Molecularly, silencing is enabled by a modular and interlocking design of the cytoplasmic domains of these potentially antagonistic receptors that predetermines the outcome of their simultaneous activation. 軸突導向II：細胞質信號途徑、軸突目標識別 Schmucker等.〈果蠅的Dscam基因是一種軸突導向受體，表現出特別的分子多樣性〉，《細胞》. 2000 Jun 9;101(6):671-84. Schmucker, et al. "Drosophila Dscam Is an Axon Guidance Receptor Exhibiting Extraordinary Molecular Diversity." Cell. 2000 Jun 9;101(6):671-84. PubMed摘要：人類唐氏綜合症細胞粘附分子(DSCAM)，在果蠅身上的同族類分子，是免疫球蛋白總科成員，它對Dock的引力把自身分離出來，Dock是SH3/SH2適應蛋白，在軸突導向中必需的物質。Dscam直接連結在Dock的SH2和SH3域。遺傳研究顯示，Dscam，Dock和絲氨酸／蘇氨酸激酶Pak一起作用，引導包含感應軸突子集的Bolwig神經到胚胎的中間目標。Dscam還需要應用在胚胎中心神經系統中軸突路徑的形成上。cDNA和染色體組分析顯示，Dscam的多形式存在伴有包括變體Ig和橫跨膜域的保存結構。另一種結合可以潛在生成超過38,000個Dscam同類物。這種分子多樣性可能造成神經元連接的特殊性。
PubMed abstract: A Drosophila homolog of human Down syndrome cell adhesion molecule (DSCAM), an immunoglobulin superfamily member, was isolated by its affinity to Dock, an SH3/SH2 adaptor protein required for axon guidance. Dscam binds directly to both Dock's SH2 and SH3 domains. Genetic studies revealed that Dscam, Dock and Pak, a serine/threonine kinase, act together to direct pathfinding of Bolwig's nerve, containing a subclass of sensory axons, to an intermediate target in the embryo. Dscam also is required for the formation of axon pathways in the embryonic central nervous system. cDNA and genomic analyses reveal the existence of multiple forms of Dscam with a conserved architecture containing variable Ig and transmembrane domains. Alternative splicing can potentially generate more than 38,000 Dscam isoforms. This molecular diversity may contribute to the specificity of neuronal connectivity. 細胞死亡和生存I：神經營養假說，生存因素/受體 Kuruvilla等.〈在交感神經元NGF信號中，PI3-K受動器途徑在空間上和功能上不同的角色〉，《神經元》. 2000 Sep;27(3):499-512. Kuruvilla, et al. "Spatially and Functionally Distinct Roles of the PI3-K Effector Pathway during NGF Signaling in Sympathetic Neurons." Neuron. 2000 Sep;27(3):499-512. Pubmed摘要：NGF是一種發展交感神經元的目標源生長遺傳因子。在此，我們指出，專門將NGF應用到交感神經元的末梢軸突上，可以導致末梢軸突和細胞體中PI3-K信號的增多。另外，NGF專有地在末梢軸突上的作用的神經元生長，比NCF直接作用在細胞體上支持神經元更依賴PI3-K。有意思的是，在細胞體和末梢軸突中的PI3-K信號都促進神經元生長。我們發現，末梢神經中的PI3-K的抑制削弱了逆行信號，這或許能解釋生長對末梢軸突中PI3-K的需要。因此，單個TrkA受動器PI3-K，在逆行NGF信號發送中空間上獨特的細胞位置有多種作用。
PubMed abstract: NGF is a target-derived growth factor for developing sympathetic neurons. Here, we show that application of NGF exclusively to distal axons of sympathetic neurons leads to an increase in PI3-K signaling in both distal axons and cell bodies. In addition, there is a more critical dependence on PI3-K for survival of neurons supported by NGF acting exclusively on distal axons as compared to neurons supported by NGF acting directly on cell bodies. Interestingly, PI3-K signaling within both cell bodies and distal axons contributes to survival of neurons. The requirement for PI3-K signaling in distal axons for survival may be explained by the finding that inhibition of PI3-K in the distal axons attenuates retrograde signaling. Therefore, a single TrkA effector, PI3-K, has multiple roles within spatially distinct cellular locales during retrograde NGF signaling. 細胞死亡和生存II：細胞死亡途徑，發展益處和病理性層面 Nakatomi等.〈缺血性腦損傷後，通過補充內生神經源而產生的海馬趾錐體神經元再生〉，《細胞》. 2002 Aug 23;110(4):429-41. Nakatomi, et al. "Regeneration of Hippocampal Pyramidal Neurons after Ischemic Brain Injury by Recruitment of Endogenous Neural Progenitors." Cell. 2002 Aug 23;110(4):429-41. PubMed摘要：成人的大腦很容易有各種損傷。然而，最近的成年哺乳動物神經起源研究發現，提出了通過恢復其潛伏再生之可能性修復受損組織的此一可能。我們指出，在栓塞性大腦損傷後，內生源的活化造成海馬趾錐體神經元的大量再生。內生源因栓塞而增生擴散，隨後移到海馬體再生新的神經元。心室內生長因素的輸灌明顯地增強這些反應，因此增加新生神經元的數量。我們的研究表明，再生神經元被結合入現有的大腦通路，可以改善神經學上的不足。這些結果擴大了中風和其他神經疾病新細胞再生療法的可能性。
PubMed abstract: The adult brain is extremely vulnerable to various insults. The recent discovery of neural progenitors in adult mammals, however, raises the possibility of repairing damaged tissue by recruiting their latent regenerative potential. Here we show that activation of endogenous progenitors leads to massive regeneration of hippocampal pyramidal neurons after ischemic brain injury. Endogenous progenitors proliferate in response to ischemia and subsequently migrate into the hippocampus to regenerate new neurons. Intraventricular infusion of growth factors markedly augments these responses, thereby increasing the number of newborn neurons. Our studies suggest that regenerated neurons are integrated into the existing brain circuitry and contribute to ameliorating neurological deficits. These results expand the possibility of novel neuronal cell regeneration therapies for stroke and other neurological diseases. 突觸傳遞I（突觸前機制） Marek和Davis.〈轉基因編碼的蛋白質光失活（F1AsH-FALI）:突觸小泡蛋白I的急性失活〉，《神經元》. 2002 Dec 5;36(5):805-1 Marek and Davis. "Transgenically Encoded Protein Photoinactivation (FlAsH-FALI): Acute Inactivation of Synaptotagmin I." Neuron. 2002 Dec 5;36(5):805-13. PubMed摘要：我們用轉基因編碼標記展示了一種蛋白質光失活的非入侵性技術。Tetracysteine修飾結合膜透螢光派生物4',5'-bis(1,3,2-dithioarsolan-2-yl)螢光素(FlAsH)並進了synaptotagmin I (Syt I4C)。神經元表達的Syt I4C零突變可以在FlAsH標記後看到，並在果蠅神經肌肉突觸中正常分佈。在488nm處，FlAsH連接Syt I4C的光在幾秒間減弱了所引起的釋放，顯示有效的螢光團輔助的Syt I光失活(FlAsH-FALI)。Syt I的失活對於光的持續是成比例變化的，遵循一階動力學。另外Syt I FlAsH-FALI是特別的，不削弱Syt I獨立的囊胞釋放。我們證明了，Syt I在囊胞釋放減弱後是必需的，但不是用來穩定減弱的囊胞狀態。
PubMed abstract: We demonstrate a noninvasive technique for protein photoinactivation using a transgenically encoded tag. A tetracysteine motif that binds the membrane-permeable fluorescein derivative 4',5'-bis(1,3,2-dithioarsolan-2-yl)fluorescein (FlAsH) was engineered into synaptotagmin I (Syt I4C). Neuronally expressed Syt I4C rescues the syt I null mutation, can be visualized after FlAsH labeling, and is normally distributed at the Drosophila neuromuscular synapse. Illumination of FlAsH bound Syt I4C at 488 nm decreases evoked release in seconds demonstrating efficient fluorophore-assisted light inactivation (FlAsH-FALI) of Syt I. The inactivation of Syt I is proportional to the duration of illumination and follows first-order kinetics. In addition, Syt I FlAsH-FALI is specific and does not impair Syt I-independent vesicle fusion. We demonstrate that Syt I is required for a post-docking step during vesicle fusion but does not function to stabilize the docked vesicle state. 突觸傳遞II（突觸後機制） Sheng和Lee.〈AMPA受體運行和突觸傳遞的控制〉，《細胞》. 2001 Jun 29;105(7):825-8. [背景和評論]. Sheng and Lee. "AMPA Receptor Trafficking and the Control of Synaptic Transmission." Cell. 2001 Jun 29;105(7):825-8. [Background and Review]. Shi等.〈在海馬趾錐體神經元裏，以其次單元體特有規則來控制AMPA受體運行至突觸鍵〉，《細胞》. 2001 May 4;105(3):331-43.[基礎文章]. Shi, et al. "Subunit-Specific Rules Governing AMPA Receptor Trafficking to Synapses in Hippocampal Pyramidal Neurons." Cell. 2001 May 4;105(3):331-43.[Primary Article]. PubMed摘要：AMPA型谷氨酸酯受體(AMPA-Rs)介導大腦裏大部分激發的突觸傳遞。在海馬趾中，大部分AMPA-Rs是異源聚合體，由GluR1/GluR2或GluR2/GluR3亞基組成。我們指出，這些AMPA-R形式顯示不同的突觸傳送機制。GluR1/GluR2受體在可塑性中加入到突觸中；這需要GluR1和I 組PDZ域蛋白的相互作用。相反地，GluR2/GluR3受體連續取代現有的突觸受體；這僅發生在已經有AMPA-Rs的突觸，還要求GluR2和NSF 、II組PDZ域蛋白的相互作用。介導的增加和突觸受體的替代相結合，可以穩定突觸效果的長期變換，可能會成為表面受體數量如何穩定和維持的普遍模型。
PubMed abstract: AMPA-type glutamate receptors (AMPA-Rs) mediate a majority of excitatory synaptic transmission in the brain. In hippocampus, most AMPA-Rs are hetero-oligomers composed of GluR1/GluR2 or GluR2/GluR3 subunits. Here we show that these AMPA-R forms display different synaptic delivery mechanisms. GluR1/GluR2 receptors are added to synapses during plasticity; this requires interactions between GluR1 and group I PDZ domain proteins. In contrast, GluR2/GluR3 receptors replace existing synaptic receptors continuously; this occurs only at synapses that already have AMPA-Rs and requires interactions by GluR2 with NSF and group II PDZ domain proteins. The combination of regulated addition and continuous replacement of synaptic receptors can stabilize long-term changes in synaptic efficacy and may serve as a general model for how surface receptor number is established and maintained. 可塑性研究的模型系統：突觸前和突觸後機制 Antonov等.〈藉單突觸PSP的運作以了解海兔回縮虹吸反射的移居性和敏感性〉，《神經科學學報》，1999 Dec 1;19(23):10438-50. [基礎文章]. Antonov, et al. "The contribution of facilitation of monostnaptic PSPs to dishabituation and sensitization of the Aplysia siphon withdrawal reflex." J Neurosci. 1999 Dec 1;19(23):10438-50. [Primary Article]. PubMed摘要：為了儘量直接地研究突觸可塑性與學習和記憶的聯繫，我們做了新的一個簡化製備，目的是研究海兔縮虹吸反射，其中較容易在學習的簡單形式中，記錄個體確定之神經元的突觸聯繫。我們估計，從LE虹吸感應神經元到LFS虹吸運動神經元的單突觸EPSPs，引發製備中大約三分之一的反射反應，這與整體動物中顯著的虹吸相對應。為了研究影響非習慣化和增強感光度的細胞機制，我們記錄了LFS神經元被激發的放電，LFS神經元刺激所產生的縮虹吸，LFS神經元裏的複合體PSP，以及行為訓練中從起作用或不起作用的LE神經元到LFS神經元。和簡化的縮腮製備不同(Cohen et al., 1997; Frost et al., 1997)，在縮虹吸製備中，我們發現在主要細胞機制，對非習慣化和增強感光度的影響不存在質的差異，我們提出之前觀察到的分裂可能出於暫態抑制，這在反射構成中不會出現。而且，在縮虹吸製備中，所有不同的分子標準，包括來自作用或者不作用的LE神經元的單突觸PSPs，都基本根據行為的變化發生改變。至今為止，這些結果最直接地證明非習慣化和增強感光度，需要多種機制的參與，包括感覺神經元運動神經元PSPs的異源性突觸易化。
PubMed abstract: To examine the relationship between synaptic plasticity and learning and memory as directly as possible, we have developed a new simplified preparation for studying the siphon-withdrawal reflex of Aplysia in which it is relatively easy to record synaptic connections between individual identified neurons during simple forms of learning. We estimated that monosynaptic EPSPs from LE siphon sensory neurons to LFS siphon motor neurons mediate approximately one-third of the reflex response measured in this preparation, which corresponds to siphon flaring in the intact animal. To investigate cellular mechanisms contributing to dishabituation and sensitization, we recorded evoked firing of LFS neurons, the siphon withdrawal produced by stimulation of an LFS neuron, the complex PSP in an LFS neuron, and the monosynaptic PSP from an "on-field" or "off-field" LE neuron to an LFS neuron during behavioral training. Unlike the simplified gill-withdrawal preparation (Cohen et al., 1997; Frost et al., 1997), in the siphon-withdrawal preparation we found no qualitative differences between the major cellular mechanisms contributing to dishabituation and sensitization, suggesting that dissociations that have been observed previously may be attributable to transient inhibition that does not occur for this component of the reflex. Furthermore, in the siphon-withdrawal preparation, all of the various cellular measures, including monosynaptic PSPs from either on-field or off-field LE neurons, changed approximately in parallel with changes in the behavior. These results provide the most direct evidence so far available that both dishabituation and sensitization involve multiple mechanisms, including heterosynaptic facilitation of sensory neuron-motor neuron PSPs. Baeumont和Zucker.〈通過環AMP與突觸前離子通道的調節以促進突觸傳遞〉，《國家神經科學》. 2000 Feb;3(2):133-41.[背景閱讀]. Baeumont and Zucker. "Enhancement of synaptic transmission by cyclic AMP modulation of presynaptic Ih channels." Nat Neurosci. 2000 Feb;3(2):133-41.[Background Reading]. PubMed摘要：腺苷酸環化酶突觸前活化和後來生成的cAMP顯示在突觸傳遞介導中的一個重要機制。很多情況下，cAMP突觸力量的中短期介導是因為蛋白激酶A的活化，以及後來前突觸離子通道或突觸蛋白的共價修飾。在此，我們指出通過血液中複合胺生成之突觸前cAMP，直接介導軸突中的超極化活性陽離子通道（Ih通道）。Ih介導使突觸力量增強，這不能僅用突觸前膜的去極來解釋。這些研究確定了一個由cAMP和Ih介導突觸可塑性的機制。
PubMed abstract: Presynaptic activation of adenylyl cyclase and subsequent generation of cAMP represent an important mechanism in the modulation of synaptic transmission. In many cases, short- to medium-term modulation of synaptic strength by cAMP is due to activation of protein kinase A and subsequent covalent modification of presynaptic ion channels or synaptic proteins. Here we show that presynaptic cAMP generation via serotonin receptor activation directly modulated hyperpolarization-activated cation channels (Ih channels) in axons. This modulation of Ih produced an increase in synaptic strength that could not be explained solely by depolarization of the presynaptic membrane. These studies identify a mechanism by which cAMP and Ih regulate synaptic plasticity. Regehr and Stevens.〈突觸傳遞生理學和短期可塑性〉，《突觸生理學》第三章 . [重要背景閱讀] [摘自神經鍵]，由Cowan, Sudhof和Stevens編輯, 2001, pp. 135-175. Regehr and Stevens. "Physiology of Synaptic Transmission and Short-Term Plasticity, Chap. 3 in Synaptic Physiology. [Important background reading] [From _Synapses_] Edited by Cowan, Sudhof, and Stevens, 2001, pp. 135-175. 神經肌肉連接處的可塑性 Barber和Lichtman,〈Activity-Driven Synapse Elimination Leads Paradoxically to Domination by Inactive Neurons." J Neurosci. 1999 Nov 15;19(22):9975-85. [Background Reading]. PubMed摘要：在出生後的生命早期，多種運動軸突在個體神經肌肉連接處積聚。然而，在出生後開始的最初幾週，一種競爭機制消去了所有輸入，只剩下一個。這種現象被稱作突觸排除，人們覺得起因是基於軸突間形式或活動水準區別的競爭（參看Lichtman,1995）。意外地，實驗資料支援活動作用的兩個相反觀點：活躍的軸突有競爭優勢（Ribchester和Taxt, 1983; Ridge和Betz, 1984; Balice-Gordon和Lichtman, 1994），而不活躍的軸突有競爭優勢（Callaway et al., 1987, 1989）。為了瞭解這種矛盾情況，我們建立了一個活動介導突觸排除模型的數學模型。我們假設介導突觸競爭的是，釋放的傳送物總數，而非釋放頻率。我們進一步假設一個神經元可以支持的總突觸面積，是由其活動水準和大小來代謝地制約的。對於發展早期有更高頻率的軸突，其競爭優勢在後期被軸突的更強突觸作用所超越，而後者的釋放速度較低。我們的數學模型通過展示這樣的事實解決了這個矛盾。此模型也提供了和操控活動實驗一致的結果，並解釋了大小原理的來源。(Henneman, 1985)。
PubMed abstract: In early postnatal life, multiple motor axons converge at individual neuromuscular junctions. However, during the first few weeks after birth, a competitive mechanism eliminates all the inputs but one. This phenomenon, known as synapse elimination, is thought to result from competition based on interaxonal differences in patterns or levels of activity (for review, see Lichtman,1995). Surprisingly, experimental data support two opposite views of the role of activity: that active axons have a competitive advantage (Ribchester and Taxt, 1983; Ridge and Betz, 1984; Balice-Gordon and Lichtman, 1994) and that inactive axons have a competitive advantage (Callaway et al., 1987, 1989). To understand this paradox, we have formulated a mathematical model of activity-mediated synapse elimination. We assume that the total amount of transmitter released, rather than the frequency of release, mediates synaptic competition. We further assume that the total synaptic area that a neuron can support is metabolically constrained by its activity level and size. This model resolves the paradox by showing that a competitive advantage of higher frequency axons early in development is overcome at later stages by greater synaptic efficacy of axons firing at a lower rate. This model both provides results consistent with experiments in which activity has been manipulated and an explanation for the origin of the size principle (Henneman, 1985). Coleman等.〈軸突回縮前突觸力的改變〉，[基礎文章], 1997. Coleman, et al. "Alterations in Synaptic Strength Preceding Axon Withdrawal." [Primary Article], 1997. 鳥鳴；運行和巡迴水平的可塑性 Boettiger和Doupe,〈在在學習鳴叫所需的鳥鳴核中，其受限發展突觸的可塑性〉，《神經元》. 2001 Sep 13;31(5):809-18.[背景閱讀]. Boettiger and Doupe, "Developmentally Restricted Synaptic Plasticity in a Songbird Nucleus Required for Song Learning." Neuron. 2001 Sep 13;31(5):809-18.[Background Reading]. PubMed摘要：我們在此提出證據，證實鳴鳥前腦區——前新紋狀體(LMAN)的側巨細胞核在學習鳴叫中，存在長期突觸可塑性。LMAN帶有迴返性間接突觸的主要神經元中成對突觸後釋放有兩個作用：阻止迴返性突觸定時NMDA受體依賴LTP，以及後突觸釋放階段激出的丘腦傳入突觸的LTD。兩種形成的可塑性都僅限於學習鳴叫的感覺關鍵期，與鳥兒在感覺學習的作用一致。觀察到的可塑性特徵很適合在LMAN中建立迴返性路徑，反映教導鳴叫激發的丘腦傳入活動的時空模式。這樣的路徑組織可以變現出，在感覺運動學習中適合鞏固某種聲音序列的教鳴記憶。
PubMed abstract: We provide evidence here of long-term synaptic plasticity in a songbird forebrain area required for song learning, the lateral magnocellular nucleus of the anterior neostriatum (LMAN). Pairing postsynaptic bursts in LMAN principal neurons with stimulation of recurrent collateral synapses had two effects: spike timing- and NMDA receptor-dependent LTP of the recurrent synapses, and LTD of thalamic afferent synapses that were stimulated out of phase with the postsynaptic bursting. Both types of plasticity were restricted to the sensory critical period for song learning, consistent with a role for each in sensory learning. The properties of the observed plasticity are appropriate to establish recurrent circuitry within LMAN that reflects the spatiotemporal pattern of thalamic afferent activity evoked by tutor song. Such circuit organization could represent a tutor song memory suitable for reinforcing particular vocal sequences during sensorimotor learning. Livingston等.〈在斑馬雀類的鳴叫學習中，不需要形成鳴叫的突觸慢NMDA-EPSC〉，《國家神經科學》. 2000 May;3(5):482-8.[基礎文章]. Livingston, et al. "Slow NMDA-EPSCs at synapses critical for song development are not required for song learning in zebra finches." Nat Neurosci. 2000 May;3(5):482-8.[Primary Article]. PubMed摘要：鳥鳴和人類話語一樣，都是通過發展的限制感覺期中聽覺的經驗學習而來。在兩個鳥類前腦核的釋放神經元中，NMDA受體介導的EPSCs (NMDA-EPSCs)在鳴叫發展中變快，這是限制學習的轉變。為了探索在學習中，這些突觸是否需要慢NMDA-EPSCs，我們延遲了鳥兒正常結束鳴叫學習的時限，孵化後（PHD）65天 ，通過把斑馬雀類從鳴叫教導者中分離出去來實現。到了PHD65，隔離鳥類的NMDA-EPSCs很快且像成年那樣，但與鳴叫教導者一起的隔離鳥類，很容易學到鳴叫。所以學習鳴叫並不需要在對鳴叫發展很重要的突觸上，存在慢NMDA-EPSC。
PubMed abstract: Birdsong, like human speech, is learned via auditory experience during a developmentally restricted sensitive period. Within projection neurons of two avian forebrain nuclei, NMDA receptor-mediated EPSCs (NMDA-EPSCs) become fast during song development, a transition posited to limit learning. To discover whether slow NMDA-EPSCs at these synapses are required for learning, we delayed song learning beyond its normal endpoint, post-hatch day (PHD) 65, by raising zebra finches in isolation from song tutors. At PHD45, before learning, isolation delayed NMDA-EPSC maturation, but only transiently. By PHD65, NMDA-EPSCs in isolates were fast and adult-like, yet isolates presented with tutors readily learned song. Thus song learning did not require slow NMDA-EPSCs at synapses critical for song development. 多模式圖和靈敏性使用依賴的擴展 Gutfreund等.〈柵門式視覺輸入至中央聽覺系統〉，《科學》. 2002 Aug 30;297(5586):1556-9.[背景閱讀]. Gutfreund, et al. "Gated Visual Input to the Central Auditory System." Science. 2002 Aug 30;297(5586):1556-9.[Background Reading]. PubMed摘要：中央聽覺系統把聲音方位提示轉譯到空間導向圖中，一部分是通過視覺經驗來實現。在穀鷹身上，該過程發生在下丘的外核(ICX)。但到現在為止，在聽覺核中還未發現有視覺活動。在此，我們指出強烈的聽覺回應很適合引導聽覺可塑性，在視覺頂蓋的抑制被禁止時出現在ICX裏。所以，抑制機制在大腦的更高層面發揮作用，視覺空間資訊通過它來選通，輸入到聽覺系統。
PubMed abstract: The central auditory system translates sound localization cues into a map of space guided, in part, by visual experience. In barn owls, this process takes place in the external nucleus of the inferior colliculus (ICX). However, to date, no trace of visual activity has been observed in this auditory nucleus. Here we show that strong visual responses, which are appropriate to guide auditory plasticity, appear in the ICX when inhibition is blocked in the optic tectum. Thus, visual spatial information is gated into the auditory system by an inhibitory mechanism that operates at a higher level in the brain. Zheng和Knudsen,〈由GABAA間接抑制的適應聽覺空間圖的功能選擇〉，《科學》. 1999 May 7;284(5416):962-5. [基礎文章]. Zheng and Knudsen, "Functional Selection of Adaptive Auditory Space Map by GABAA-Mediated Inhibition." Science. 1999 May 7;284(5416):962-5. [Primary Article]. PubMed摘要：穀鷹下丘外核包含一個空間的聽覺形態，這是基於神經元對聲音時速耳間差別的介導。在雛鷹身上，該腦區可以獲得耳間時間差的另一些形態，這是非常態經驗造成的。我們已發現到，在表達學習之後非正常形態的外核中，以正常形態為基礎的路徑仍然存在，但因為A型氨酪酸（GABAA）受體的抑制而無法運作。這樣的失活，是由於網路特定輸入通道不適當的強抑制造成的。所以，在抑制形式中由經驗產生的變化，以及在興奮形式中的調整，都對中央神經系統適應可塑性起著關鍵作用。
PubMed abstract: The external nucleus of the inferior colliculus in the barn owl contains an auditory map of space that is based on the tuning of neurons for interaural differences in the timing of sound. In juvenile owls, this region of the brain can acquire alternative maps of interaural time difference as a result of abnormal experience. It has been found that, in an external nucleus that is expressing a learned, abnormal map, the circuitry underlying the normal map still exists but is functionally inactivated by inhibition mediated by gamma-aminobutyric acid type A (GABAA) receptors. This inactivation results from disproportionately strong inhibition of specific input channels to the network. Thus, experience-driven changes in patterns of inhibition, as well as adjustments in patterns of excitation, can contribute critically to adaptive plasticity in the central nervous system. 非皮質視覺域的可塑性 Sin等.〈視覺活動增加的樹枝狀結晶生長需要NMDA受體和Pho GTP酶〉，《自然》. 2002 Oct 3;419(6906):475-80.[基礎文章]. Sin, et al. "Dendrite growth increased by visual activity requires NMDA receptor and Rho GTPases." Nature. 2002 Oct 3;419(6906):475-80.[Primary Article]. PubMed摘要：之前的研究表明，神經元活動可能引導重要神經系統突觸連接的發展，通過包含谷氨酸酯受體，和GTPase決定的肌動蛋白細胞骨架介導的機制進行。在此，我們使用視覺非洲爪蟾蝌蚪頂蓋細胞活體延時成像證明，輕微刺激下增強的視覺活動促進樹突棘生長。刺激誘發的樹突棘生長，需要谷氨酸酯受體介導的突觸傳遞，減少的RhoA活動和增加的Rac和Cdc42活動。結果顯示Rho GTPases在由活體視覺刺激產生之結構可塑性中的作用。
PubMed abstract: Previous studies suggest that neuronal activity may guide the development of synaptic connections in the central nervous system through mechanisms involving glutamate receptors and GTPase-dependent modulation of the actin cytoskeleton. Here we demonstrate by in vivo time-lapse imaging of optic tectal cells in Xenopus laevis tadpoles that enhanced visual activity driven by a light stimulus promotes dendritic arbor growth. The stimulus-induced dendritic arbor growth requires glutamate-receptor-mediated synaptic transmission, decreased RhoA activity and increased Rac and Cdc42 activity. The results delineate a role for Rho GTPases in the structural plasticity driven by visual stimulation in vivo. Zhang等.〈視覺輸入可誘導在生長中連接視網膜和中腦頂蓋神經纖維突觸的長期增強〉，《國家神經科學》. 2000 Jul;3(7):708-15. [背景閱讀]. Zhang, et al. "Visual input induces long-term potentiation of developing retinotectal synapses." Nat Neurosci. 2000 Jul;3(7):708-15. [Background Reading]. PubMed摘要：早期視覺經驗對發展神經連接的改善很重要。從爪蟾蝌蚪頂蓋記錄的活體整細胞顯示，在對側眼的重複低亮度刺激導致谷氨酸輸入的持續增強，但頂蓋神經元的GABA能或甘氨酸能的輸入則不然。這樣的增強可以促進連接視網膜和中腦頂蓋神經纖維的突觸增強。這需要突觸後頂蓋細胞的脈衝和NMDA受體活化，並有效閉塞連接視網膜和中腦頂蓋神經纖維的突觸長期的增強（LTP），這是由視網膜活動中心細胞的直接電激誘發的。所以，LTP這類突觸修飾可以通過自然視覺輸入誘發，可能成為發展連接依賴活動之改善的基本系統之一部分。
PubMed abstract: Early visual experience is essential in the refinement of developing neural connections. In vivo whole-cell recording from the tectum of Xenopus tadpoles showed that repetitive dimming-light stimulation applied to the contralateral eye resulted in persistent enhancement of glutamatergic inputs, but not GABAergic or glycinergic inputs, on tectal neurons. This enhancement can be attributed to potentiation of retinotectal synapses. It required spiking of postsynaptic tectal cells as well as activation of NMDA receptors, and effectively occluded long-term potentiation (LTP) of retinotectal synapses induced by direct electrical stimulation of retinal ganglion cells. Thus, LTP-like synaptic modification can be induced by natural visual inputs and may be part of the underlying mechanism for the activity-dependent refinement of developing connections. 視覺皮層的可塑性：歷史與爭議 Hata等人編著，〈當貓的視覺皮層被以藥理學方式抑制的同時，主傳入神經活性也有選擇性的刪減〉， 《神經元》 1999 Feb;22(2):375-81. [基礎文章]。 Hata, et al. "Selective Pruning of More Active Afferents When Cat Visual Cortex Is Pharmacologically Inhibited." Neuron. 1999 Feb;22(2):375-81. [Primary Article]. PubMed摘要：人們認為，依賴活動的競爭引導神經連接特定模式的正常發展。這樣的競爭普遍歡迎更多主動輸入，把這些輸入變得更大、更強，同時較少的輸入則變得更小、更弱。我們在藥理上抑制視覺皮層細胞的活動，並在一眼閉上時測量針對雙目的三維輸入結構。更主動的輸入針對睜開的眼睛，這種輸入變得比針對閉上眼睛被剝奪的輸入少，這和正常動物的情況很相似。這些發現說明了，在活體中，不是傳入活動的數量；而是皮層和傳入活動的相互關係，調控這些輸入的增長或收回。
PubMed abstract: Activity-dependent competition is thought to guide the normal development of specific patterns of neural connections. Such competition generally favors more active inputs, making them larger and stronger, while less active inputs become smaller and weaker. We pharmacologically inhibited the activity of visual cortical cells and measured the three-dimensional structure of inputs serving the two eyes when one eye was occluded. The more active inputs serving the open eye actually became smaller than the deprived inputs from the occluded eye, which were similar to those in normal animals. These findings demonstrate in vivo that it is not the amount of afferent activity but the correlation between cortical and afferent activity that regulates the growth or retraction of these inputs. Rittenhouse 等人編著，〈單眼視力抽離引發視覺皮層突觸長期萎縮〉，《自然雜誌》. 1999 Jan 28;397(6717):347-50. [背景閱讀]. Rittenhouse, et al. "Monocular deprivation induces homosynaptic long-term depression in visual cortex." Nature. 1999 Jan 28;397(6717):347-50. [Background Reading]. PubMed摘要：出生後早期發展中短暫的單眼視力剝奪可導致突觸傳遞減弱，這樣可以使視覺皮層神經元鈍化，影響之後剝奪視力的眼睛之視覺刺激。Bienenstock-Cooper-Munro (BCM)理論提出，長期抑制效應（LTD）同源性突觸機制是剝奪影響的原因。從定義上看，同源性突觸抑制只出現在活性突觸中。因此，與平常的觀點不同，單眼視力剝奪引起的突觸抑制只是視網膜失活的一個結果，這個理論框架指出，突觸抑制或許確實是由視覺剝奪的視網膜殘餘活動產生的。在此，我們對這個觀點的真實性進行了研究，比較了把眼瞼縫合短暫單眼視力剝奪的結果，和用河豚毒素進行眼睛內處理的分子失活結果。眼瞼縫合讓視網膜自然作用，該處河豚毒素除去所有活動。和BCM理論一致，我們的結果顯示，單眼眼瞼縫合引起被剝奪視力眼睛反應在小貓視覺皮層的抑制，這比用河豚毒素進行抑制的作用更大。這些發現在新皮層依賴經驗的可塑性機制上有重要意義。
PubMed abstract: Brief monocular deprivation during early postnatal development can lead to a depression of synaptic transmission that renders visual cortical neurons unresponsive to subsequent visual stimulation through the deprived eye. The Bienenstock-Cooper-Munro (BCM) theory proposes that homosynaptic mechanisms of long-term depression (LTD) account for the deprivation effects. Homosynaptic depression, by definition, occurs only at active synapses. Thus, in contrast to the commonly held view that the synaptic depression caused by monocular deprivation is simply a result of retinal inactivity, this theoretical framework indicates that the synaptic depression may actually be driven by the residual activity in the visually deprived retina. Here we examine the validity of this idea by comparing the consequences of brief monocular deprivation by lid suture with those of monocular inactivation by intra-ocular treatment with tetrodotoxin. Lid suture leaves the retina spontaneously active, whereas tetrodotoxin eliminates all activity. In agreement with the BCM theory, our results show that monocular lid suture causes a significantly greater depression of deprived-eye responses in kitten visual cortex than does treatment with tetrodotoxin. These findings have important implications for mechanisms of experience-dependent plasticity in the neocortex. 皮質可塑性的分子機制 Hensch等.〈視覺皮質形成中，依賴經驗的可塑性的局部GABA巡迴控制〉，《科學》. 1998 Nov 20;282(5393):1504-8.[基礎文章]. Hensch, et al. "Local GABA Circuit Control of Experience-Dependent Plasticity in Developing Visual Cortex." Science. 1998 Nov 20;282(5393):1504-8.[Primary Article]. PubMed摘要：生命早期的感覺經驗影響了哺乳動物的大腦形成。在大鼠模型中，確定了發展的視覺皮層功能連接依賴活動的改善中存在損傷。谷氨酸脫羧酶的同源形成的面向基因的分裂，防止對短時剝奪視力單眼反應的全部喪失，而不會影響活體突觸修飾的合作機制。具選擇性的，顱骨快速抑制傳遞的依賴使用的改善和苯二氮恢復的活體可塑性一起，對遺傳缺陷進行補救。視覺皮層的抑制中間神經元特殊網路，可能探測到感覺輸入的混亂，引發發展中依賴經驗的可塑性。
PubMed abstract: Sensory experience in early life shapes the mammalian brain. An impairment in the activity-dependent refinement of functional connections within developing visual cortex was identified here in a mouse model. Gene-targeted disruption of one isoform of glutamic acid decarboxylase prevented the competitive loss of responsiveness to an eye briefly deprived of vision, without affecting cooperative mechanisms of synapse modification in vitro. Selective, use-dependent enhancement of fast intracortical inhibitory transmission with benzodiazepines restored plasticity in vivo, rescuing the genetic defect. Specific networks of inhibitory interneurons intrinsic to visual cortex may detect perturbations in sensory input to drive experience-dependent plasticity during development. Kilman等.〈活性降失減低微型IPSC強度乃是經由減少在新生皮質中後突觸GABAA受體叢的數量〉，《神經科學學報》.2002 Feb 15;22(4):1328-37.[背景閱讀], 2002. Kilman, et al. "Activity Deprivation Reduces Miniature IPSC Amplitude by Decreasing the Number of Postsynaptic GABAA Receptors Clustered at Neocortical Synapses." J Neurosci. 2002 Feb 15;22(4):1328-37.[Background Reading], 2002. PubMed摘要：維持興奮和抑制間適度的平衡是很必要的，可預防突然失語或癲癇的產生。通過一個機制，皮層網路可以維持這樣的平衡，這個機制是通過依賴活動的抑制調控，但這是否首先通過突觸數量或突觸力量達到的就尚未清楚。先前，我們已發現，培育的視覺皮層錐體神經元上，活動剝奪的2d增加微型EPSCs (mEPSCs)的振幅。此時我們發現到，這相同的操作減低mIPSCs的振幅。這種情況出現在單通道導率沒變化，但伴有mIPSC高峰期通道打開的平均數下降，以及突觸後位置GABA(A)受體(GABA(A)Rs)著色度的下降。另外，突觸點的數量表示，在活動阻閉後GABA(A)Rs可見的水準下降了約50%，雖然突觸前接觸的總數沒有下降。這些資料表明，活動剝奪通過降低GABA(A)Rs在突觸點聚集的數量，和功能抑制突觸的數量減低皮層抑制。因為興奮和抑制突觸電流被活動阻閉在相反方向調控，這些資料說明，興奮和抑制之間的平衡是由正在進行的活動動態調控的。
PubMed abstract: Maintaining the proper balance between excitation and inhibition is necessary to prevent cortical circuits from either falling silent or generating epileptiform activity. One mechanism through which cortical networks maintain this balance is through the activity-dependent regulation of inhibition, but whether this is achieved primarily through changes in synapse number or synaptic strength is not clear. Previously, we found that 2 d of activity deprivation increased the amplitude of miniature EPSCs (mEPSCs) onto cultured visual cortical pyramidal neurons. Here we find that this same manipulation decreases the amplitude of mIPSCs. This occurs with no change in single-channel conductance but is accompanied by a reduction in the average number of channels open during the mIPSC peak and a reduction in the intensity of staining for GABA(A) receptors (GABA(A)Rs) at postsynaptic sites. In addition, the number of synaptic sites that express detectable levels of GABA(A)Rs was decreased by approximately 50% after activity blockade, although there was no reduction in the total number of presynaptic contacts. These data suggest that activity deprivation reduces cortical inhibition by reducing both the number of GABA(A)Rs clustered at synaptic sites and the number of functional inhibitory synapses. Because excitatory and inhibitory synaptic currents are regulated in opposite directions by activity blockade, these data suggest that the balance between excitation and inhibition is dynamically regulated by ongoing activity. 可塑性和GABA間接抑制 Hardingham等.〈突觸外的NMDAR通過觸發CREB脫離和細胞死亡途徑因而與突觸NAMDAR迴異〉，《國家神經科學》. 2002 May;5(5):405-14.[背景閱讀]. Hardingham, et al. "Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways." Nat Neurosci. 2002 May;5(5):405-14.[Background Reading]. PubMed摘要：在此，我們指出，突觸和突觸外NMDA (N-甲基-D-天冬氨酸鹽)受體對CREB（cAMP反應成分粘合蛋白）功能及基因調節、神經元存活有反作用。鈣通過突觸外NMDA受體進入，誘發CREB活動和大腦產生的向神經因數（BDNF）基因表達，和L型鈣通道的刺激一樣強烈。相對而言，鈣通過突觸外NMDA受體進入，受液體谷氨酸接觸或缺氧缺血環境的觸發，啟動一般支配的CREB閉合通道，關閉BDNF表達的感應。突觸NMDA受體有抗凋亡活動，其中突觸外NMDA受體刺激引致線粒體膜電壓（谷氨酸酯引起的神經傷害的早期標記）降低和細胞死亡。突觸外NMDA受體特定阻閉，可能有效預防中風和其他帶谷氨酸毒素之神經疾病後的神經元減少。
PubMed abstract: Here we report that synaptic and extrasynaptic NMDA (N-methyl-D-aspartate) receptors have opposite effects on CREB (cAMP response element binding protein) function, gene regulation and neuron survival. Calcium entry through synaptic NMDA receptors induced CREB activity and brain-derived neurotrophic factor (BDNF) gene expression as strongly as did stimulation of L-type calcium channels. In contrast, calcium entry through extrasynaptic NMDA receptors, triggered by bath glutamate exposure or hypoxic/ischemic conditions, activated a general and dominant CREB shut-off pathway that blocked induction of BDNF expression. Synaptic NMDA receptors have anti-apoptotic activity, whereas stimulation of extrasynaptic NMDA receptors caused loss of mitochondrial membrane potential (an early marker for glutamate-induced neuronal damage) and cell death. Specific blockade of extrasynaptic NMDA receptors may effectively prevent neuron loss following stroke and other neuropathological conditions associated with glutamate toxicity. Owens等.〈由短桿菌肽穿孔斑記錄和鈣成像以顯示胚胎和新生皮質部分的興奮性GABA反應〉，《神經科學學報》. 1996 Oct 15;16(20):6414-23.[基礎文章]. Owens, et al. "Excitatory GABA Responses in Embryonic and Neonatal Cortical Slices Demonstrated by Gramicidin Perforated-Patch Recordings and Calcium Imaging." J Neurosci. 1996 Oct 15;16(20):6414-23.[Primary Article]. PubMed摘要：大腦部分的短桿菌肽穿孔片鉗記錄，用於獲得胚胎中GABBA受體逆向電壓(EGABAA)發展改變的精確估計，以及出生後大鼠早期新生皮層細胞，包括神經上皮先驅細胞、皮層板神經元和出生後新皮層神經元的估計。我們的研究結果顯示，在EGABB中有不斷發展的負轉移，帶有在最新的皮層先驅細胞中所發現之最積極的價值。在新皮層發展的早期，EGABBA由氯化物(Cl-)梯度決定，內在氯化物濃度([Cl-]i)隨發展而減少。EGABBA對靜止電壓是積極的，指出GABA用來為發展中的皮層細胞去極化。和這樣的結論一致，我們發現，含蠅蕈醇的GABBA受體活化，可以增加胚胎和出生後早期新皮層細胞的內在鈣濃度([Ca2+]i)，這通過電壓選通的鈣通道(VGCCs)來實現的。出生後的細胞顯示出自然產生的突觸後突觸電流，由荷包牡丹堿甲碘化物(BMI)消除，而非谷氨酸受體抗體，並且在氯平衡勢上逆轉。同樣，短暫的[Ca2+]i自然上升對BMI和TTX敏感，可以在相同年齡上觀察到，這顯示出內聖突觸GABBA受體活化可以為細胞去極化，並活化VGCCs。這些結果表明，GABBA受體介導的去極化或許影響早期新皮層發展，包括神經發生和突觸發生，通過依賴Ca(2+)的信號傳導通道的活化實現。
PubMed abstract: Gramicidin perforated-patch-clamp recordings in brain slices were used to obtain an accurate assessment of the developmental change in the GABAA receptor reversal potential (EGABAA) in embryonic and early postnatal rat neocortical cells including neuroepithelial precursor cells, cortical plate neurons, and postnatal neocortical neurons. Our results demonstrate that there is a progressive negative shift in EGABAA with the most positive values found in the youngest cortical precursor cells. At the early stages of neocortical development, EGABAA is determined by the chloride (Cl-) gradient, and the internal chloride concentration ([Cl-]i) decreases with development. EGABAA is positive to the resting potential, indicating that GABA serves to depolarize developing neocortical cells. Consistent with this conclusion, GABAA receptor activation with muscimol was found-to increase the internal calcium concentration ([Ca2+]i) in both embryonic and early postnatal neocortical cells through the activation of voltage-gated calcium channels (VGCCs). Postnatal cells exhibit spontaneous postsynaptic synaptic currents, which are eliminated by bicuculline methiodide (BMI) but not glutamate receptor antagonists and reverse at the Cl- equilibrium potential. Likewise, brief spontaneous increases in [Ca2+]i, sensitive to BMI and TTX, are observed at the same ages, suggesting that endogenous synaptic GABAA receptor activation can depolarize cells and activate VGCCs. These results suggest that GABAA receptor-mediated depolarization may influence early neocortical developmental events, including neurogenesis and synaptogenesis, through the activation of Ca(2+)-dependent signal transduction pathways. |