Inhibition as a Binary Switch for Excitatory Plasticity in Pyramidal Neurons

Synaptic plasticity is thought to induce memory traces in the brain that are the foundation of learning. To ensure the stability of these traces in the presence of further learning, however, a regulation of plasticity appears beneficial. Here, we take up the recent suggestion that dendritic inhibition can switch plasticity of excitatory synapses on and off by gating backpropagating action potentials (bAPs) and calcium spikes, i.e., by gating the coincidence signals required for Hebbian forms of plasticity. We analyze temporal and spatial constraints of such a gating and investigate whether it is possible to suppress bAPs without a simultaneous annihilation of the forward-directed information flow via excitatory postsynaptic potentials (EPSPs). In a computational analysis of conductance-based multi-compartmental models, we demonstrate that a robust control of bAPs and calcium spikes is possible in an all-or-none manner, enabling a binary switch of coincidence signals and plasticity. The position of inhibitory synapses on the dendritic tree determines the spatial extent of the effect and allows a pathway-specific regulation of plasticity. With appropriate timing, EPSPs can still trigger somatic action potentials, although backpropagating signals are abolished. An annihilation of bAPs requires precisely timed inhibition, while the timing constraints are less stringent for distal calcium spikes. We further show that a wide-spread motif of local circuits—feedforward inhibition—is well suited to provide the temporal precision needed for the control of bAPs. Altogether, our model provides experimentally testable predictions and demonstrates that the inhibitory switch of plasticity can be a robust and attractive mechanism, hence assigning an additional function to the inhibitory elements of neuronal microcircuits beyond modulation of excitability.

突触可塑性（Synaptic plasticity）被认为可在大脑中诱导构成学习基础的记忆痕迹（memory traces）。然而，为确保这些痕迹在后续学习过程中保持稳定，对可塑性的调控似乎是有益的。本文借鉴近期提出的相关假说，即树突抑制（dendritic inhibition）可通过门控反向传播动作电位（backpropagating action potentials, bAPs）与钙尖峰（calcium spikes）——亦即门控赫布型可塑性（Hebbian forms of plasticity）所需的重合信号（coincidence signals）——来开启或关闭兴奋性突触（excitatory synapses）的可塑性。我们分析了此类门控机制的时空约束（temporal and spatial constraints），并探究了是否可在不通过兴奋性突触后电位（excitatory postsynaptic potentials, EPSPs）同时阻断前向信息流的前提下，抑制反向传播动作电位。在基于电导的多室模型（conductance-based multi-compartmental models）的计算分析中，我们证明，可通过全或无方式（all-or-none manner）实现对反向传播动作电位与钙尖峰的稳健调控，从而实现重合信号与可塑性的二元切换。抑制性突触在树突树（dendritic tree）上的位置决定了其效应的空间范围，并允许实现可塑性的通路特异性调控（pathway-specific regulation）。在合适的时序下，即便反向传播信号被阻断，兴奋性突触后电位仍可触发体细胞动作电位（somatic action potentials）。阻断反向传播动作电位需要精准时序的抑制作用，而对远端钙尖峰的时序约束则相对宽松。我们进一步证明，神经环路中广泛存在的前馈抑制（feedforward inhibition）基序，非常适于提供调控反向传播动作电位所需的时序精度。综上，我们的模型给出了可通过实验验证的预测，并证明可塑性的抑制性开关可成为一种稳健且极具吸引力的机制，从而为神经元微环路（neuronal microcircuits）的抑制性组分赋予了除调控兴奋性之外的额外功能。