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.
  突触可塑性是指，在大脑中的突触连接可以模式活动(patterned activity)的刺激下改变其连接强度(形态和功能上的修饰)。
• 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.
  持久的突触可塑性、长时程增强、长时程抑制，这三种形式的突触连接改变介导了神经环路中有关刺激的信息存储
• 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.
  最初人们关注海马谷氨酸能突触的 long-term plasticity。然而，越来越多的研究证据表明 long-term plasticity 不仅在海马区，也不仅在谷氨酸能神经元。在 GABA能神经元(抑制性神经元)，在新皮层、小脑以及其他亚环路脑区也有发现 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.
  形式和机制多样的持久型突触可塑性表明，经历事件和神经活动而刺激改变突触连接效能是突触的基本特性。这对学习和记忆非常关键

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)
  在海马的 穿通通路(perforant path) 给予短暂高频的刺激 (100Hz)，会引起海马齿状回颗粒细胞持续的(几小时到数天)的场兴奋性突触后电位(field excitatory postsynaptic potential, fEPSP), 这种现象称为 长时程增强(long-term potentiation, LTP)
• The sign of the plasticity depends on the frequency of the stimulation.
  是增强还是抑制，取决于刺激的频率(有个阈值)和时机

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)
  在刺激海马 CA1区锥形神经细胞的试验中，当以高频的电流(100Hz)刺激传入神经时，会产生LTP。而当以低频的电流(1Hz)刺激时会产生 LTD。这表明突触可塑具有双向性。

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 刺激能引起海马的 LTP，但对新皮层无效。而 TBS (theta burst stimulation) 能引起很多脑区的 LTP，包括海马，视皮层，嗅皮层以及在小脑颗粒细胞的mossy输入纤维上。(然而还是没有明白什么是 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)引起神经细胞去极化或超级化(神经元的)，从而产生各种形式的突触可塑性。 因为，刺激和突触前后膜各组分的配合对于产生 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.
  高频刺激一定引起 LTP，低频刺激一定引起 LTD 吗？

timing 时机

• 关于 action potential, EPSP, IPSP的解释
  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).
  突触前膜的动作电位可以引发 EPSP(兴奋性突触后电位) 或 IPSP(抑制性突触后电位)

• 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 试验中发现，如果突触前动作电位早于兴奋性的突触后电位，则两个神经元间单个突触的连接效率会增强，反之，如果 EPSP 先于 spike (动作电位)，这突触连接减弱。

？？？？ 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 可能还受突触前膜输入位置，与突触后膜接受位置的影响

• 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 的规则会因为 突触前后配对的频率 以及 动作电位次数而改变？？(不知道怎么翻译)
  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 细胞/分子机制

• 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 都是依赖活动 (activity-dependent)的长时程可塑性家族，包括一系列的分子机器。不同的模式活动，不同状态的神经元，不同的发育状态，都会参与到 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.
  最初在海马谷氨酸能突触的研究中发现，介导 LTP 需要 NMDA 受体. NMDA 对谷氨酸和膜的去极化都敏感。

• 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. 须看

• LTP and LTD are both postsynaptically expressed.
  LTP和 LTD都是突触后表达

• 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 给予强刺激时能激活 突触后的NMDA 受体，引起 Ca2+迅速内流，从而激活钙调蛋白激酶(CAMKII) 和 其他第二信使，最终达到平衡？并且 突触后的AMPA受体会增加。
相反，在低频的刺激下触发的是 LTD，Ca2+内流速度和容量都较小，最终导致 AMPA 受体的减少。

?? tetanic stimulation
?? TBS stimulation
？？AMPA receptor 增加或减少有什么影响

• 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 能神经元和谷氨酸神经元突触可塑性形成的方式.png
GABA能神经元：LTPi 和 LTDi (双向的可塑性)
Glutamatergic神经元：突触前的可塑性，突触后的可塑性。（具体机制有点笼统，还需细看）

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.
  当把突触可塑性放到环路中考虑时，我们需要注意参与的 “神经调控因子”。如，谷氨酸能神经元的可塑性能力不是仅仅取决于即将发生的特定的行为输入，而可能还取决于其他网络组建。

• 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).
  另一个在环路互作中的突触性需要考虑homosynaptic plasticity 和heretosynaptic plasticity。one input may affect other elements of the circuit

• A 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
  第三个影响突触可塑性能力的是在诱导 LTP 产生之前，下游的信号同时是否已经被激活。(若被占用，LTP 不能产生)

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 能抑制神经元突触可塑性(异突触可塑性)，需要激活 突触后膜的 NMDA 受体 或 mGluRs 受体
• 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.
  参与 GABA能神经输入的 异突触LTP和 LTD，包括逆行可溶性分子，如内源性大麻素，一氧化氮(NO)，或其他神经生长因子以及一些(共激活的受体？)

?? GABA能神经输入(GABAergic inputs)

• review: Nugent & Kauer, 2008 ; Younts & Castillo, 2014

• 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 能神经元也能诱导同突触抑制性可塑性。和* 异突触*的方式很不一样 。取决于刺激的行为模式，配对的，依赖Ca2+的，不依赖钙离子的信号通路会参与其中。

• 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能神经元的可塑性是双向的(既能 LTP 也能 LTD)，部分诱导产生 LTD 抑制递质释放的机制是通过大麻素受体以及钙调蛋白磷酸激活酶信号的作用

• GABAergic inhibitory synaptic plasticity contribute to learning processes
  GABA能 抑制性神经元的突触可塑性 和学习记忆形成有关

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.

特定的模式活动会使 兴奋性突触 和 抑制性突触 修改它们的突触连接效率。这个修改的痕迹会被保留并成为局部环路中一种长期存储的形式，最终形成所谓的 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.
  兴奋性突触 和 抑制性突触 在健康人的神经回路中维持一种平衡的状态。因此，参与这些机制的部件都必须到位，才能共同调节或协调 依赖于经验experience-dependent 和依赖于学习learning-dependent 产生的神经环路的变化

？？？ experience-dependent & learning-dependent