Computational modeling reveals dendritic origins of GABA(A)-mediated excitation in CA1 pyramidal neurons.
Computational modeling reveals dendritic origins of GABA(A)-mediated excitation in CA1 pyramidal neurons.
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计算建模揭示了CA1锥体神经元中GABA（A）介导的激发的树突状起源。
DOI：
10.1371/journal.pone.0047250
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Clancy CE
中科院分区：
文献类型：
--
作者：
Lewin N;Aksay E;Clancy CE
GABA是成人中枢神经系统中的关键抑制性神经递质，但在某些情况下可导致矛盾兴奋，其在从内分泌应激反应到兴奋性疾病（包括神经性疼痛和颞叶癫痫）的多种病理学中有因果关系。我们进行了一个计算建模的方法，以确定合理的离子机制的GABA依赖性兴奋在孤立的突触后CA 1海马神经元，因为它可能构成一个触发病理同步癫痫样放电。特别是，在促进GABAA介导的兴奋中，通过GABAA受体的细胞内氯积累和通过K/Cl共转运蛋白KCC 2的细胞外钾积累的相互作用是复杂的。在实验上，很难确定去极化电流的离子机制，因为钾瞬变对分离GABA具有挑战性，并且许多GABA信号传导发生在小的、难以测量的树突隔室中。为了解决这个问题，并确定合理的离子机制GABAA介导的兴奋，我们建立了一个详细的生物病理学现实模型的CA 1锥体神经元，包括离子稳态的关键过程。我们的研究结果表明，在树突状细胞室，但不是在体细胞室，氯积累是足以引起显着的去极化的GABAA逆转电位和占主导地位的碳酸氢根电流，提供了大量的电流源，以驱动全细胞去极化。模型模拟预测，细胞外K+瞬变可以增强GABAA介导的兴奋，但不会引起它。我们的模型还表明，潜在的GABAA介导的兴奋，以促进网络的同步性取决于中间神经元突触的位置-兴奋性正反馈可以发生时，中间神经元突触到远端树突隔室，而中间神经元投射到perisomatic区域将导致抑制。
GABA is the key inhibitory neurotransmitter in the adult central nervous system, but in some circumstances can lead to a paradoxical excitation that has been causally implicated in diverse pathologies from endocrine stress responses to diseases of excitability including neuropathic pain and temporal lobe epilepsy. We undertook a computational modeling approach to determine plausible ionic mechanisms of GABAA-dependent excitation in isolated post-synaptic CA1 hippocampal neurons because it may constitute a trigger for pathological synchronous epileptiform discharge. In particular, the interplay intracellular chloride accumulation via the GABAA receptor and extracellular potassium accumulation via the K/Cl co-transporter KCC2 in promoting GABAA-mediated excitation is complex. Experimentally it is difficult to determine the ionic mechanisms of depolarizing current since potassium transients are challenging to isolate pharmacologically and much GABA signaling occurs in small, difficult to measure, dendritic compartments. To address this problem and determine plausible ionic mechanisms of GABAA-mediated excitation, we built a detailed biophysically realistic model of the CA1 pyramidal neuron that includes processes critical for ion homeostasis. Our results suggest that in dendritic compartments, but not in the somatic compartments, chloride buildup is sufficient to cause dramatic depolarization of the GABAA reversal potential and dominating bicarbonate currents that provide a substantial current source to drive whole-cell depolarization. The model simulations predict that extracellular K+ transients can augment GABAA-mediated excitation, but not cause it. Our model also suggests the potential for GABAA-mediated excitation to promote network synchrony depending on interneuron synapse location - excitatory positive-feedback can occur when interneurons synapse onto distal dendritic compartments, while interneurons projecting to the perisomatic region will cause inhibition.
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