Heterosynaptic Plasticity: Multiple Mechanisms and Multiple Roles

classification: Literature_Reading/synaptic_plasticity

keyword: synaptic plasticity; runaway dynamics; weight normalization

outline

• Introduction: what is homosynaptic plasticity and Heterosynaptic plasticity 什么是同突触可塑性，什么是异突触可塑性
• The function of them 有什么功能
• Mechanisms of Heterosynaptic Plasticity 机制是什么

Introduction

Homosynaptic plasticity(red inputs). occurs at synapses that were directly involved in activation of a cell during the induction. Induction of homosynaptic plasticity at a synapse requires its presynaptic activation. This form of plasticity is also called input specific or associative.
同突触可塑性 是指在诱导可塑性过程中，被激活的突触发生变化。(直接参与)

？？Hebbian-type learning rules.

Heterosynaptic plasticity(green) can be induced at synapses that were not active during the induction. Thus, any synapse at a cell can be subject to heterosynaptic plasticity after episodes of strong postsynaptic activity.

异突触可塑性 是指在诱导可塑性过程中，未被激活的突触发生变化。(临近的影响)。 在发生一个强烈的突触后事件时，任何突触都服从异突触可塑性 。

Figure 1. 同突触可塑性 和 异突触可塑性 触发机制示意图.png

Homosynaptic plasticity mediates associative modifications of synaptic weights. Heterosynaptic plasticity counteracts runaway dynamics introduced by Hebbian-type rules and balances synaptic changes.

同突触可塑性调节突触的权重，异突触可塑性抵消 Hebbian-type 规则的作用，并维持突触改变的平衡。

Hebbian-type learning rules

• When an axon of cell A is near enough to excite cell B or repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A’s efficiency, as one of the cells firing B, is increased.
  突触前神经元向突触后神经元的持续重复的刺激，可以导致突触传递效能的增加

• Hebb’r rule:
  Hebb 认为，如果两个临近的神经元重复或持续被同时激活( take part in firing)或被抑制，它们之间的相关的权重(联系)会增强，相反，如果一个被激活，另一个没有(do not take part in firing)，则他们的联系会减弱。如果这两个神经元没什么联系，它们间的联系权重不变

  • synaptic weights change:改变突触的权重
    • synaptic connections that repeatedly or persistently take part in firing of the postsynaptic neuron increase their strength
    • synapses that consistently do not take part in firing the postsynaptic neuron decrease their strength
  • cooperativity:协调性
    • activation should be strong, exceeding a certain threshold, to induce plastic changes (超过一定阈值才能触发突触可塑性)
  • input specificity: 特定位置的信号输入
    • changes take place only at synapses that were activated during the induction but not at other synapses

• STDP learning rule is one of homosynaptic plasticity

  • synaptic inputs that were active shortly before a postsynaptic action potential (pre before post) are potentiated, whereas synaptic inputs active shortly after the postsynaptic spike (post before pre) are depressed. (multiple presynaptic and one postsynaptic spikes)
    突触输入先于突触后动作电位，增强；
    突触输入慢于突触后动作电位，抑制。
    在多个突触前对应一个突触后的模型下适用。
  • Spike-timing dependent plasticity (STDP) explicitly implements relative timing between firing of the neuron and activity at its inputs (presynaptic spikes) as a determinant of the direction and the magnitude of synaptic weight changes.

• With symmetrical STDP learning rule (Fig. 4A) synaptic weights showed runaway dynamics.
  STDP 也会引起 synaptic runaway dynamics

Functional Roles for Homosynaptic Plasticity

• Plasticity governed by Hebbian-type learning is input-specific, or homosynaptic
  Hebbian型学习掌管的突触可塑性是特异性突触的，同突触的。

• homosynaptic plasticity is believed to provide a cellular mechanism underlying processes of new memory formation and learning.
  同突触可塑性被认为是新记忆形成和学习的细胞机制

Why Heterosynaptic Plasticity Is Required in Addition to Hebbian-Type Learning Rules

two major drawbacks of Hebbian-type learning

• Hebbian-type learning rules have intrinsic positive feedback
  正反馈，调控不便 (强则更强，弱者更弱)
• Hebbian-type learning rules introduce only a weak degree of competition between synapses. (require repetition of specific patterns of the input activity)
  需要重复的特定刺激才能改变突触的权重(可塑性)

The requirements for both stabilization and competition can be solved by introducing heterosynaptic plasticity—changes at synapses that were not active during plasticity induction
由于Hebbian-type learning 的不足，所以需要 异突触可塑性 来维持稳定(防止神经元兴奋/抑制失控 runaway dynamics)和竞争(兴奋和抑制)的平衡。有了异突触可塑性后，任一一个突触的权重发生改变，其他突触的权重也会跟着修改，最后使总体保持平衡。

Functional Roles for Heterosynaptic Plasticity 1

• Heterosynaptic LTD accompanying the induction of homosynaptic LTP clearly has potential for both balancing plastic changes and supporting synaptic competition.
  伴随着 同突触长时程增强(homosynaptic LTP) 的 异突触长时程抑制(Heterosynaptic LTD)具有平衡突触可塑变化和支撑突触竞争的功能。

• Heterosynaptic LTP was first discovered at synapses adjacent to potentiated inputs. LTP protocols induce plasticity not only at the activated synapses but also at those not active during the induction.
  异突触 LTP 在接受增强输入的邻居突触被发现，这表明，LTP 不仅能在被激活的突触产生，还能在未能激活的突触产生 (???? 突触前膜还是后膜？后膜到胞体？)

Figure2 异突触可塑性的试验证据

spatial distribution of plastic changes

• Induction of LTP in the hippocampus or amygdala at a set of synapses was accompanied by a biphasic profile of heterosynaptic changes (figure2 c): a weaker LTP at nearby inputs, LTD at more distant inputs, and finally no changes at yet more distantly located synapses
  在海马或杏仁核诱导产生的LTP 能诱导临近的异突触产生两种状态的可塑性(图2 c)， 在兴奋性输入附近是较弱的 LTP，较远的是 LTD，更远的地方不会产生变化。

• A symmetrical profile was observed around the site of LTD induction: weaker LTD at close distances and LTP at more distant inputs.
  若诱导产生的是 LTD，机制和 LTP 相似，近距离的是较弱的 LTD，较远距离的是 LTP

• Long-term plasticity can be induced by rises of intracellular calcium concentration produced by photolysis of caged calcium (figure2d). The direction of plastic changes in these experiments depended on the dynamics of intracellular calcium signal: large increases of [Ca2+]in could induce LTP, and smaller amplitude prolonged [Ca2+]in increases could lead to LTD.
  异突触可塑性的产生可以不依赖于突触前膜。细胞内钙浓度的变化就能决定可塑性的方向：高浓度 Ca2+诱导 LTP，低浓度 Ca2+诱导 LTD

• Long-term plastic changes can be also induced by intracellular tetanization—bursts of spikes evoked by short depolarizing pulses applied through the recording electrode

  • what is intracellular tetanization ??????????????
  • Each neuron in the neocortex receives thousands of synaptic inputs. Repetitive activation of a fraction of these inputs, few dozens to hundreds, can lead to repetitive firing of a cell and under certain conditions induce synaptic plasticity. During the induction, all synapses but for those of the activated fraction will experience postsynaptic activity without activation of their presynaptic fibers. This situation, postsynaptic activity without presynaptic activation, is mimicked by the intracellular tetanization. ???
  • intracellular tetanization 是模拟 在‘’没有突触前膜刺激下，突触后膜的活动‘’

• Intracellular tetanization simultaneously induced LTP in one input and LTD in the other.

  • The direction of plastic changes was correlated with initial paired-pulse ratio, which is inversely related to the release probability.

  • Inputs that expressed high initial paired-pulse ratio, and thus had low release probability, were typically potentiated. Inputs that expressed low initial paired-pulse ratio, and thus had high release probability, were typically depressed or did not change.

  • Weak synaptic inputs with low release probability, for example, because they underwent depression in the past, have a stronger predisposition for potentiation. Strong synapses with high release probability, such as those recently potentiated, have higher predisposition for depression.

  • intracellular tetanization 可以同时引起 LTP 和 LTD 向同一个 neuron 输入

  • paired-pulse paradigm ????????

  • high initial paired-pulse ratio ???

  • 弱突触的刺激输入伴随着低概率的递质释放，然而这样的突触具有更强的 增强易化性，这意味着，如果给一个强刺激 (Intracellular tetanization) 会更容易诱导 LTP 产生。同理，强突触具有更高的 抑制易化性

BCM RULE
metaplasticity

• history dependent changes of the abilities of synapses ( heterosynaptic plasticity)
• Weight dependence of synaptic plasticity ( homosynaptic plasticity )

??tetanization

Figure 3. 由intracellular tetanization (钛电极，双脉冲) 诱导产生的长时程突触可塑性

• To summarize, heterosynaptic plasticity induced by intracellular tetanization expresses properties that are well suited for serving as a robust mechanism of normalization of synaptic weights: (a) it depresses strong and potentiates weak synapses thus preventing runaway dynamics of synaptic weights, (b) it can be induced at non-active synapses, and (c) it operates on the same time scale as homosynaptic plasticity.

由intracellular tetanization 引起的异突触可塑性表明了这个将突触权重标准化机制的特性。

1. 异突触可塑性 能 抑制强突触， 增强弱突触，防止runaway dynamics of synaptic weights的发生
2. 它能在非活动的突触被诱导产生，
3. 它和同突触可塑(homosynaptic plasticity)在同一个时间范围发生

Functional Roles for Heterosynaptic Plasticity 2

1. First, it can play a stabilizing role by effectively counteracting positive feedback introduced by Hebbian-type learning rules, and thus prevent runaway dynamics of synaptic weight and neuronal firing.
   首先，异突触可塑性在 Hebbian-type learning 引起的正反馈突触改变的情况下起重要的稳定作用，能有效地阻止突触权重和神经元放电的 runaway dynamics.
   • One consequence of this robust stabilization is that it makes a broad variety of learning rules and input activity patterns compatible with normal, unsaturated operation of learning networks.
     这个有力的稳定角色产生的一个效果是：形成众多学习规则和行为输入模式，与非饱和的学习网络正常运作相兼容 (相辅相成)
   • Another consequence is that weight-dependent heterosynaptic plasticity endorses any excessive activity in the system with stabilizing effect.
     另一个结果是 依赖权重的异突触可塑性兼容稳定系统中偶然出现的过激活动？？
   • Finally, by preventing saturation of synaptic weights, heterosynaptic plasticity keeps synapses within their operation range, susceptible to further changes, and thus keeps the system susceptible to new learning.
     最后，异突触可塑性能防止突触权重饱和(0/1)，使突触处于正常运作的范围，为新的学习保有足够的空间。

2. Second, heterosynaptic plasticity can support and facilitate synaptic competition by introducing an additional force driving synaptic weights toward equilibrium.
   异突触可塑性能支撑和加强突触的竞争，是促使突触权重(synaptic weights)平衡的一股额外力量
   • If STDP is not operating at a synapse, say, because it is not activated presynaptically, its weight will be shifted toward the heterosynaptic plasticity equilibrium.
     如果一个突触没被 STDP 激活，则会它的权重会被 heterosynaptic 修改以达到可塑性的平衡

3. Two further forms of heterosynaptic changes have been described and well documented: changes of excitability and homeostatic plasticity.

• excitability 兴奋性：
  • homeostatic nature
  • decreasing excitability after prolonged strong activity but increasing it after activity suppression
  • enhance or amplify effects of potentiation by increasing excitability of the dendrites at which tetanized synapses are located
• Homeostatic plasticity 可塑性稳态
  • Vitureira and others 2012
  • it requires nonspecific dramatic changes of neuronal activity
  • it operates on a very long time scale

Computational Properties of Plasticity Induced by Intracellular Tetanization

• The model neuron consisted of two compartments, axosomatic and dendritic, and received synaptic inputs from 100 simulated presynaptic neurons (Fig. 4A)
  实验的神经元模型由胞体轴突和树突构成，突触后膜细胞接受100个神经元突触前输入
• With symmetrical STDP learning rule (Fig. 4A) synaptic weights showed runaway dynamics. (Fig. 4B) Heterosynaptic plasticity with experimentally observed properties effectively prevented runaway dynamics of synaptic weights and activity. (Fig. 4C)
  根据对称的 STDP learning rule, 突触的权重会 runaway dynamics. 而异突触可塑性能具有阻止这种突触权重和活动 runaway dynamics 的特性

Figure4. 实验证明Heterosynaptic plasticity 能防止突触权重的runaway dynamics

Mechanisms of Heterosynaptic Plasticity

Rise of intracellular calcium concentration is an obvious candidate for triggering heterosynaptic plasticity
提高细胞内钙离子浓度是触发异突触可塑性的扳机

• Substantial rise of [Ca2+] in is produced by bursts of back-propagating action potentials activating voltage- dependent calcium channels, and can be further amplified by calcium release from internal stores.
  细胞大量 ca2+ 的提升是由于反向传播(back-propagating)的动作电位激活了钙离子电压门控通道，同时 ca2+提升的效应会进一步被细胞内储存的ca2+放大

back-propagating ??

• The resulting profile of [Ca2+] in may promote induction of heterosynaptic LTP at sites of strong calcium rise, and LTD at sites of more moderate rise.
  Ca2+ 浓度提升高的位置会诱导异突触 LTP 产生，而中等强度的(较弱的)ca2+ 浓度提升则会诱导 异突触 LTD 产生

• However, the final outcome, LTP or LTD, might be also strongly influenced by predispositions of synapses for plasticity, because both potentiation and depression could be induced at synapses presumably located at similar distances and thus experiencing similar calcium rises
  然而，最后表现出来时 LTP和 LTD，受到突触易性影响很大，因为相近的突触(尤其是离 activity site 远的)可能 ca2+提升的水平相差不大，增强或抑制都可能被诱导产生。

• In addition, heterosynaptic changes can be induced by cell-wide signals, such as [Ca2+] in rises produced by backpropagating action potentials.
  全细胞范围的信号

Plasticity induced is required retrograde signaling (presynaptic components)
可塑性需要逆行的信号

• One candidate retrograde messenger is nitric oxide (NO) , mediating local heterosynaptic plasticity of both excitatory and inhibitory transmission.
  NO 是其中一个逆行的信号分子，调节局部的异突触可塑的 兴奋性递质传递 和 抑制性递质传递

• NO signaling required strong postsynaptic activity
  NO 信号需要很强的突触后激活

• Activation of metabotropic glutamate receptors (mGluRs) can trigger the production, release, and retrograde action of endocannabinoids, including heterosynaptic LTD at inhibitory synapses
  eCB 能被代谢型葡萄糖受体(mGluRs) 激活而被产生、释放并逆行作用于突触前膜，引起抑制性突触处的异突触 LTD

• Heterosynaptic depression can be also mediated by activity-dependent release of ATP and adenosine from neurons and astrocytes.
  异突触抑制也能通过神经元和星形胶质细胞介导的活动依赖( activity-dependent )释放的 ATP 和腺苷诱导产生

• Most of these mechanisms overlap with those mediating homosynaptic plasticity

Mexican-hat profile？？？？

conclusion

• Homosynaptic plasticity is induced by specific patterns of input activity such as high-frequency tetanization for LTP or prolonged low-frequency stimulation for LTD, or specific timing relative to postsynaptic spikes for STDP. Homosynaptic changes mediate associative learning, but they also drive synaptic weights to the extreme values, bringing the system out of balance.
  Homosynaptic plasticity 可以由特定的行为输入模式诱导产生，包括 高频tetanization 诱导产生的 LTP，持续低频刺激诱导产生的 LTD，或特殊时机动作电位诱导产生的 STDP。同突触的改变影响这关联学习的效果，但同时也会是突触的权重偏离，走向极端。

• Heterosynaptic plasticity drive synaptic weights away from the extremes, toward an equilibrium within the operation range
  异突触可行性就是想消除这种偏离，使突触权重回到能正常运作的平衡状态

• The weight of a synapse is determined by the balance between the homosynaptic and heterosynaptic plasticity forces.
  突触的权重由 homosynaptic plasticity 和 heterosynaptic plasticity 这两个力量的平衡最终决定

Outlook and Open Questions

• What determines the balance between homosynaptic and heterosynaptic plasticity at individual synapses and in neuronal networks?
• What are synapse-specific, cell type- specific, and structure-specific mechanisms of maintaining this balance?
• How is the balance between homosynaptic and heterosynaptic plasticity regulated, and what factors may disturb it?

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• How is the balance between homosynaptic and heterosynaptic plasticity regulated during development?

During formation of sensory representations, runaway dynamics may be a useful process contributing to elimination of excessive connections while preserving the “correct” synapses

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• What determines the predispositions of synapses for potentiation and depression, and what are mechanisms of weight-dependence of both homosynaptic and heterosynaptic plasticity?
• how is long-term stability of connections mediating life-long memory traces achieved in the face of the multitude of plasticity mechanisms driving homosynaptic and heterosynaptic changes?
• How can some synapses escape the drive for modifications imposed by these forces?