Long-Term Potentiation and Long-Term Depression
Literature_Reading/synaptic_plasticity
What is synaptic plasticity ?
- Synaptic connections in the brain can change their strength in response to patterned activity. This ability of synapses is defined as synaptic plasticity.
突觸可塑性是指，在大腦中的突觸連接可以模式活動(patterned activity)的刺激下改變其連接強度(形態和功能上的修飾)。 - Long lasting forms of synaptic plasticity, long-term potentiation (LTP), and long-term depression (LTD), are thought to mediate the storage of information about stimuli or features of stimuli in a neural circuit.
持久的突觸可塑性、長時程增強、長時程抑制，這三種形式的突觸連接改變介導了神經環路中有關刺激的信息存儲 - Long-term plasticity presents not only in hippocampal glutamatergic synapses. There is now extensive evidence that long-term plasticity can be induced at glutamatergic and GABAergic synapses in neocortex cerebellum, cerebellum, and subcortical circuits.
最初人們關注海馬谷氨酸能突觸的 long-term plasticity。然而，越來越多的研究證據表明 long-term plasticity 不僅在海馬區，也不僅在谷氨酸能神經元。在 GABA能神經元(抑制性神經元)，在新皮層、小腦以及其他亞環路腦區也有發現 LTP. - The widespread capacity for long-term plasticity and the diversity of mechanisms indicate that the ability to change synaptic efficacy in an activity-dependent manner is a fundamental property of synapses throughout the brain.
形式和機制多樣的持久型突觸可塑性表明，經歷事件和神經活動而刺激改變突觸連接效能是突觸的基本特性。這對學習和記憶非常關鍵
What is LTP?
- In the first report about activity-dependent long-term plasticity it was shown that high frequency stimulation of the perforant path produced a long lasting increase in the field potential response and in the number of population spikes in the dentate gyrus of the hippocampus. This form of long lasting plasticity became known as long-term potentiation (LTP)
在海馬的 穿通通路(perforant path) 給予短暫高頻的刺激 (100Hz)，會引起海馬齒狀回顆粒細胞持續的(幾小時到數天)的場興奮性突觸后電位(field excitatory postsynaptic potential, fEPSP), 這種現象稱為 長時程增強(long-term potentiation, LTP) - The sign of the plasticity depends on the frequency of the stimulation.
是增強還是抑制，取決于刺激的頻率(有個閾值)和時機
How to induce LTP or LTD?
frequency
- Stimulating the afferent fibers onto CA1 pyramidal neurons in the hippocampus, LTP was induced when stimuli were delivered at high frequency (100 stimuli at 100 Hz), while the same number of stimuli delivered at low frequency (1 Hz) induced a long-term depression of the evoked response (LTD)
在刺激海馬 CA1區錐形神經細胞的試驗中，當以高頻的電流(100Hz)刺激傳入神經時，會產生LTP。而當以低頻的電流(1Hz)刺激時會產生 LTD。這表明突觸可塑具有雙向性。
theta frequency/ theta burst stimulation, TBS ?
4–7 Hz
Tetanic stimulation ?2–3 trains of 1s stimuli at 100 Hz
Tetanic stimulation (2–3 trains of 1s stimuli at 100 Hz) was an effective induction paradigm in the hippocampus, but not in neocortex . Differently, TBS stimulation effectively induced LTP in many regions of the brain including the hippocampus, visual cortex, olfactory cortex, and at the mossy fiber input onto cerebellar granule cells.
Tetanic 刺激能引起海馬的 LTP，但對新皮層無效。而 TBS (theta burst stimulation) 能引起很多腦區的 LTP，包括海馬，視皮層，嗅皮層以及在小腦顆粒細胞的mossy輸入纖維上。(然而還是沒有明白什么是 TBS)
Patterned stimulation on the depolarizing phase or on the hyperpolarizing phase of a neuronal oscillation would produce different forms of plasticity. The need for depolarization for successful LTP induction indicated that both the afferent input and the postsynaptic neuron needed to be active for potentiation to occur, while LTD was induced if the activity of the pre-and postsynaptic components were uncorrelated.
特定的刺激(Patterned stimulation)引起神經細胞去極化或超級化(神經元的)，從而產生各種形式的突觸可塑性。 因為，刺激和突觸前后膜各組分的配合對于產生 LTP 和 LTD 是必需的Recent studies challenged the view that high frequency stimulation is necessary for LTP induction, while low frequency stimulation is necessary for LTD.
高頻刺激一定引起 LTP，低頻刺激一定引起 LTD 嗎？
timing 時機
關于 action potential, EPSP, IPSP的解釋
When an action potential reaches the presynaptic membrane, it triggers the release of chemicals called neurotransmitters. These neurotransmitters can affect the postsynaptic membrane in one of two ways. They either initiate an excitatory postsynaptic potential (EPSP) or an inhibitory postsynaptic potential (IPSP).
突觸前膜的動作電位可以引發 EPSP(興奮性突觸后電位) 或 IPSP(抑制性突觸后電位)If the action potential of the presynaptic neuron (such glutamatergic synapses) preceded the excitatory postsynaptic potential (EPSP) the efficacy of the monosynaptic connection between the two neurons was increased. When the EPSP/spike order was reversed the strength of the connection was decreased
在1997 Markram 試驗中發現，如果突觸前動作電位早于興奮性的突觸后電位，則兩個神經元間單個突觸的連接效率會增強，反之，如果 EPSP 先于 spike (動作電位)，這突觸連接減弱。
？？？？ 后者的 EPSP 是什么引起的
- STDP: spike timing dependent plasticity
- t-LTD: time-dependent LTD (long-term depression)
- t-LTP: time-dependent LTP (long-term potention)
Further studies demonstrated that the STDP rule can be affected by the location of the activated presynaptic input along the dendritic harbor of the postsynaptic pyramidal neuron.
STDP 可能還受突觸前膜輸入位置，與突觸后膜接受位置的影響STDP can also show variations to the pre-post timing rule if the frequency of pre-post pairing or the number of pre- and postsynaptic spikes is changed (Buchanan & Mellor, 2010 ).
STDP 的規則會因為 突觸前后配對的頻率 以及 動作電位次數而改變？？(不知道怎么翻譯)
For instance, in the hippocampus, pairing of single pre-and postsynaptic spikes STDP at or above 10 Hz induces t-LTP independently of pre-and postsynaptic order (Buchanan & Mellor, 2010 ); while t-LTD only is induced if the pairing is below 10 Hz (Wittenberg & Wang, 2006 ).
How LTP and LTD maintains?
Cellular Mechanisms for LTP and LTD 細胞/分子機制
both LTP and LTD constitute families of activity-dependent long-term plastic changes, including a wide range of mechanisms that can be engaged depending on the pattern of activity, state of the neuron, and developmental stage
LTP 和 LTD 都是依賴活動 (activity-dependent)的長時程可塑性家族，包括一系列的分子機器。不同的模式活動，不同狀態的神經元，不同的發育狀態，都會參與到 LTP 和 LTD 中。Initially focusing on hippocampal glutamatergic synapses, it was shown that the induction of LTP requires the activation of a special type of glutamatergic receptor, the NMDA receptor, which is sensitive to simultaneous glutamate binding and membrane depolarization.
最初在海馬谷氨酸能突觸的研究中發現，介導 LTP 需要 NMDA 受體. NMDA 對谷氨酸和膜的去極化都敏感。NMDA receptors activation allows calcium inflow. Calcium acts as a second messenger that activates a number of molecules involved in trafficking receptors at synapses, as well as signaling cascades that can activate gene transcription
Herring, B. E., & Nicoll, R. A. (2016). Long-term potentiation: From CaMKII to AMPA receptor trafficking. Annual Review of Physiology, 78, 351–365. 須看
LTP and LTD are both postsynaptically expressed.
LTP和 LTD都是突觸后表達Strong activation of postsynaptic NMDA receptors by tetanic or TBS stimulation increases intracellular calcium rapidly (Lisman, 2001 ). Such rapid change in intracellular calcium triggers activation of the calcium calmodulin kinase II (CAMKII) (Lisman, 1994 ) and other second messenger cascades that ultimately lead to the stabilization and increase in the number of postsynaptic AMPA receptors (Takahashi et al., 2003 ). Differently, the low frequency stimulation used for inducing LTD increases intracellular calcium concentration slowly and to a lesser extent than a high frequency paradigm (Lisman, 2001 ). This slow increase in calcium activates signaling pathways leading to the removal of AMPA receptors
Tetanic or TBS 給予強刺激時能激活 突觸后的NMDA 受體，引起 Ca2+迅速內流，從而激活鈣調蛋白激酶(CAMKII) 和 其他第二信使，最終達到平衡？并且 突觸后的AMPA受體會增加。
相反，在低頻的刺激下觸發的是 LTD，Ca2+內流速度和容量都較小，最終導致 AMPA 受體的減少。
?? tetanic stimulation
?? TBS stimulation
？？AMPA receptor 增加或減少有什么影響
- NMDA-independent forms of plasticity
- presynaptically expressed forms of LTP and LTD
- depending on the state of the connection (Ward et al., 2006 )
- postnatal development
- For example, in layer 4 of rodent primary visual cortex, recurrent glutamatergic synapses show two forms of LTD in the third postnatal week, both expressed presynaptically. One is induced by an STDP paradigm and depends on the activation of metabotropic glutamate receptors (mGluR); the other is induced by repetitive presynaptic bursting and depends on presynaptic NMDA receptors (Wang et al., 2012 ).
GABA能神經元：LTPi 和 LTDi (雙向的可塑性)
Glutamatergic神經元：突觸前的可塑性，突觸后的可塑性。（具體機制有點籠統，還需細看）
Synaptic Plasticity in Local Circuits
When considering synaptic plasticity in the context of a circuit, one important additional level of regulation to be considered depends on the presence of neuromodulators (?? What is neuromodulators). The capacity for plasticity of glutamatergic synapses is not uniquely dependent on the incoming pattern of activity of a specific input, but may also depend on other network components.
當把突觸可塑性放到環路中考慮時，我們需要注意參與的 “神經調控因子”。如，谷氨酸能神經元的可塑性能力不是僅僅取決于即將發生的特定的行為輸入，而可能還取決于其他網絡組建。Another important factor to consider when looking at plasticity in the context of circuit interactions is that patterns of activity that drive the induction of plasticity at one input (homosynaptic plasticity) can also affect neighboring inputs (heretosynaptic plasticity).
另一個在環路互作中的突觸性需要考慮homosynaptic plasticity 和heretosynaptic plasticity。one input may affect other elements of the circuitA third important factor that can affect the capacity for plasticity of glutamatergic synapses is whether signaling pathways were activated prior to the induction of LTP
第三個影響突觸可塑性能力的是在誘導 LTP 產生之前，下游的信號同時是否已經被激活。(若被占用，LTP 不能產生)
Long-Term Plasticity at GABAergic Inhibitory Synapses
- The activity requirements and mechanisms for GABAergic synaptic plasticity are quite diverse.
- These forms of inhibitory plasticity require either the additional activation of NMDA receptors or of metabotropic glutamate receptors (mGluRs) on the postsynaptic neuron.
谷氨酸激活引起 GABA 能抑制神經元突觸可塑性(異突觸可塑性)，需要激活 突觸后膜的 NMDA 受體 或 mGluRs 受體 - A number of signaling mechanisms have been implicated in heterosynaptic LTP and LTD of GABAergic inputs, including signaling by retrograde diffusible molecules such as endocannabinoids, nitric oxide, or brain derived neurotrophic factor and co-activation of receptors for neuromodulators.
參與 GABA能神經輸入的 異突觸LTP和 LTD，包括逆行可溶性分子，如內源性大麻素，一氧化氮(NO)，或其他神經生長因子以及一些(共激活的受體？)
?? GABA能神經輸入(GABAergic inputs)
Homosynaptic inhibitory plasticity can also be induced at GABAergic synapses. Depending on the pattern of activity of the pairing, calcium-dependent mechanisms (Holmgren & Zilberter, 2001 ) or calcium independent (Wang & Maffei, 2014 ) signaling pathways can be engaged.
GABA 能神經元也能誘導同突觸抑制性可塑性。和* 異突觸*的方式很不一樣 。取決于刺激的行為模式，配對的，依賴Ca2+的，不依賴鈣離子的信號通路會參與其中。GABAergic plasticity is also bidirectional, and some of the mechanisms for LTD of inhibitory transmission include signaling via cannabinoid receptors (Chevaleyre & Castillo, 2003 ) and calcium-calcineurin signaling.
GABA能神經元的可塑性是雙向的(既能 LTP 也能 LTD)，部分誘導產生 LTD 抑制遞質釋放的機制是通過大麻素受體以及鈣調蛋白磷酸激活酶信號的作用GABAergic inhibitory synaptic plasticity contribute to learning processes
GABA能 抑制性神經元的突觸可塑性 和學習記憶形成有關
conclusion
- The ability to induce LTP and LTD in response to patterned activity allows excitatory and inhibitory synapses in the brain to modify their efficacy and keep a trace of these modifications as a form of long-term storage within local circuits.
特定的模式活動會使 興奮性突觸 和 抑制性突觸 修改它們的突觸連接效率。這個修改的痕跡會被保留并成為局部環路中一種長期存儲的形式，最終形成所謂的 LTP 和 LTD
- Excitatory and inhibitory synaptic drive is thought to be in balance in healthy functioning neural circuits, thus mechanisms must be in place to co-regulate or coordinate experience-dependent and learning-dependent changes in both components.
興奮性突觸 和 抑制性突觸 在健康人的神經回路中維持一種平衡的狀態。因此，參與這些機制的部件都必須到位，才能共同調節或協調 依賴于經驗experience-dependent 和依賴于學習learning-dependent 產生的神經環路的變化
？？？ experience-dependent & learning-dependent
