Takkala Petri, Zhu Yi, Prescott Steven A
Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Ontario, Canada.
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
PLoS Comput Biol. 2016 Nov 11;12(11):e1005215. doi: 10.1371/journal.pcbi.1005215. eCollection 2016 Nov.
The central terminals of primary afferent fibers experience depolarization upon activation of GABAA receptors (GABAAR) because their intracellular chloride concentration is maintained above electrochemical equilibrium. Primary afferent depolarization (PAD) normally mediates inhibition via sodium channel inactivation and shunting but can evoke spikes under certain conditions. Antidromic (centrifugal) conduction of these spikes may contribute to neurogenic inflammation while orthodromic (centripetal) conduction could contribute to pain in the case of nociceptive fibers. PAD-induced spiking is assumed to override presynaptic inhibition. Using computer simulations and dynamic clamp experiments, we sought to identify which biophysical changes are required to enable PAD-induced spiking and whether those changes necessarily compromise PAD-mediated inhibition. According to computational modeling, a depolarizing shift in GABA reversal potential (EGABA) and increased intrinsic excitability (manifest as altered spike initiation properties) were necessary for PAD-induced spiking, whereas increased GABAAR conductance density (ḡGABA) had mixed effects. We tested our predictions experimentally by using dynamic clamp to insert virtual GABAAR conductances with different EGABA and kinetics into acutely dissociated dorsal root ganglion (DRG) neuron somata. Comparable experiments in central axon terminals are prohibitively difficult but the biophysical requirements for PAD-induced spiking are arguably similar in soma and axon. Neurons from naïve (i.e. uninjured) rats were compared before and after pharmacological manipulation of intrinsic excitability, and against neurons from nerve-injured rats. Experimental data confirmed that, in most neurons, both predicted changes were necessary to yield PAD-induced spiking. Importantly, such changes did not prevent PAD from inhibiting other spiking or from blocking spike propagation. In fact, since the high value of ḡGABA required for PAD-induced spiking still mediates strong inhibition, we conclude that PAD-induced spiking does not represent failure of presynaptic inhibition. Instead, diminished PAD caused by reduction of ḡGABA poses a greater risk to presynaptic inhibition and the sensory processing that relies upon it.
初级传入纤维的中枢终末在GABAA受体（GABAAR）激活时会发生去极化，因为它们细胞内的氯离子浓度维持在电化学平衡之上。初级传入去极化（PAD）通常通过钠通道失活和分流来介导抑制，但在某些条件下可诱发动作电位。这些动作电位的逆向（离心）传导可能导致神经源性炎症，而正向（向心）传导在伤害性纤维的情况下可能导致疼痛。PAD诱导的动作电位被认为会克服突触前抑制。我们通过计算机模拟和动态钳实验，试图确定哪些生物物理变化是PAD诱导动作电位所必需的，以及这些变化是否必然损害PAD介导的抑制。根据计算模型，GABA反转电位（EGABA）的去极化偏移和内在兴奋性增加（表现为动作电位起始特性改变）是PAD诱导动作电位所必需的，而GABAAR电导密度（ḡGABA）增加则有混合效应。我们通过动态钳将具有不同EGABA和动力学的虚拟GABAAR电导插入急性分离的背根神经节（DRG）神经元胞体中，对我们的预测进行了实验测试。在中枢轴突终末进行类似的实验极其困难，但PAD诱导动作电位的生物物理要求在胞体和轴突中可能相似。比较了来自未受伤（即未受损）大鼠的神经元在药理学操纵内在兴奋性前后的情况，并与来自神经损伤大鼠的神经元进行了比较。实验数据证实，在大多数神经元中，两种预测的变化都是产生PAD诱导动作电位所必需的。重要的是，这些变化并没有阻止PAD抑制其他动作电位或阻止动作电位传播。事实上，由于PAD诱导动作电位所需的高ḡGABA值仍介导强烈的抑制作用，我们得出结论，PAD诱导的动作电位并不代表突触前抑制失败。相反，由ḡGABA降低导致的PAD减弱对突触前抑制和依赖于它的感觉处理构成了更大的风险。
