Two developmental switches in GABAergic signalling:: the K+-Cl- cotransporter KCC2 and carbonic anhydrase CAVII
Two developmental switches in GABAergic signalling:: the K+-Cl- cotransporter KCC2 and carbonic anhydrase CAVII
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DOI：
10.1113/jphysiol.2004.077495
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发表时间：
2005-01-01
影响因子：
5.5
通讯作者：
Kaila, K
中科院分区：
文献类型：
--
作者：
Rivera, C;Voipio, J;Kaila, K
GABA能信号传导具有“离子可塑性”的独特性质，其基于突触后神经元中Cl-和HCO 3-离子浓度的短期和长期变化。虽然短期离子可塑性是由活性依赖性，通道介导的阴离子位移，长期离子可塑性取决于表达模式的变化和参与阴离子稳态的分子的动力学调节。在开发过程中，GABA能传递的去极化/兴奋对超极化/抑制受两种关键分子的神经元表达的影响：氯化物-挤压K+-Cl-共转运蛋白KCC 2和胞质碳酸酐酶（CA）同种型CAVIL在大鼠海马锥体神经元中，KCC 2的急剧上调解释了“发育开关”，其在出生后第二周结束时将未成熟神经元的去极化和兴奋性GABA反应转化为经典的超极化抑制。未成熟的海马产生大规模的网络活动，这是取消在平行的上调KCC 2和随之而来的增加神经元Cl-挤出的功效。在出生后第12天（P12）左右，锥体内CAVII表达突然急剧增加，促进由强烈GABA能活性诱发的兴奋性反应。这主要是由GABA能钾瞬变引起的，导致空间广泛的神经元去极化和同步尖峰放电。这些事实表明CAVII是用作抗癫痫药物的CA抑制剂的假定靶点。KCC 2在成年大鼠神经元中的表达在癫痫样活动和/或BDNF/TrkB信号传导引起的神经元损伤后下调膜相关KCC 2的寿命非常短，在几十分钟的范围内，这使得KCC 2非常适合介导GABA能离子可塑性。此外，影响KCC 2的运输和动力学调节以及CAVII的激活/失活的因素是GABA能反应的离子调节中的明显候选者。在成熟神经元的病理生理条件下（癫痫，损伤）的KCC 2的下调似乎反映了早期发育机制的“重演”，这可能是在受损的bra-in组织中重建连接的先决条件。
GABAergic signalling has the unique property of 'ionic plasticity', which is based on short-term and long-term changes in the Cl- and HCO3- ion concentrations in the postsynaptic neurones. While short-term ionic plasticity is caused by activity-dependent, channel-mediated anion shifts, long-term ionic plasticity depends on changes in the expression patterns and kinetic regulation of molecules involved in anion homeostasis. During development the efficacy and also the qualitative nature (depolarization/excitation versus hyperpolarization/ inhibition) of GABAergic transmission is influenced by the neuronal expression of two key molecules: the chloride-extruding K+-Cl- cotransporter KCC2, and the cytosolic carbonic anhydrase (CA) isoform CAVIL In rat hippocampal pyramidal neurones, a steep up-regulation of KCC2 accounts for the 'developmental switch, which converts depolarizing and excitatory GABA responses of immature neurones to classical hyperpolarizing inhibition by the end of the second postnatal week. The immature hippocampus generates large-scale network activity, which is abolished in parallel by the up-regulation of KCC2 and the consequent increase in the efficacy of neuronal Cl- extrusion. At around postnatal day 12 (P 12), an abrupt, steep increase in intrapyramidal CAVII expression takes place, promoting excitatory responses evoked by intense GABAergic activity. This is largely caused by a GABAergic potassium transient resulting in spatially widespread neuronal depolarization and synchronous spike discharges. These facts point to CAVII as a putative target of CA inhibitors that are used as antiepileptic drugs. KCC2 expression in adult rat neurones is down-regulated following epileptiform activity and/or neuronal damage by BDNF/TrkB signalling. The lifetime of membrane-associated KCC2 is very short, in the range of tens of minutes, which makes KCC2 ideally suited for mediating GABAergic ionic plasticity. In addition, factors influencing the trafficking and kinetic modulation of KCC2 as well as activation/deactivation of CAVII are obvious candidates in the ionic modulation of GABAergic responses. The down-regulation of KCC2 under pathophysiological conditions (epilepsy, damage) in mature neurones seems to reflect a 'recapitulation' of early developmental mechanisms, which may be a prerequisite for the re-establishment of connectivity in damaged bra-in tissue.