Experimental studies have indicated that prolonged ketamine exposure in neonates at anesthetic doses causes neuronal apoptosis, which contributes to long-term impairments of learning and memory later in life. The neuronal excitotoxicity mediated by compensatory upregulation of N-methyl-D-aspartate receptors (NMDARs) is proposed to be the underlying mechanism. However, this view does not convincingly explain why excitotoxicity-related apoptotic injury develops selectively in immature neurons. We proposed that the GABAA receptors (GABAARs)-mediated excitatory synaptic signaling due to high expression of the Na⁺-K⁺-2Cl- co-transporter (NKCC1), occurring during the early neuronal development period, plays a distinct role in the susceptibility of immature neurons to ketamine-induced injury. Using whole-cell patch-clamp recordings from the forebrain slices containing the anterior cingulate cortex, we found that in vivo repeated ketamine administration significantly induced neuronal hyperexcitability in neonatal, but not adolescent, rats. Such hyperexcitability was accompanied by the increase both in GABAAR- and NMDAR-mediated synaptic transmissions. An interference with the NKCC1 by bumetanide treatment completely reversed these enhanced effects of ketamine exposure and blocked GABAAR-mediated postsynaptic current activity. Thus, these findings were significant as they showed, for the first time, that GABAAR-mediated excitatory action may contribute distinctly to neuronal excitotoxic effects of ketamine on immature neurons in the developing brain.

实验研究表明，在麻醉剂量的新生儿中，氯胺酮的长时间暴露会导致神经元凋亡，这会导致以后生命的长期学习和记忆障碍。N甲基-D-天冬氨酸受体（NMDARs）的补偿性上调介导的神经元兴奋性毒性是潜在的机制。但是，这种观点不能令人信服地解释为什么在未成熟的神经元中选择性发生兴奋性毒性相关的细胞凋亡。我们提出，由于Na ⁺ -K ^+的高表达，GABAA受体（GABAARs）介导的兴奋性突触信号传导。-2Cl-转运蛋白（NKCC1）发生在神经元发育的早期阶段，在未成熟神经元对氯胺酮诱导的损伤的敏感性中起着独特的作用。从含有前扣带皮层的前脑切片使用全细胞膜片钳记录中，我们发现，在体内重复服用氯胺酮可明显诱导新生大鼠（而非青春期）的神经元过度兴奋。这种过度兴奋伴随着GABAAR和NMDAR介导的突触传递的增加。布美他尼治疗对NKCC1的干扰完全逆转了氯胺酮暴露的这些增强效应，并阻断了GABAAR介导的突触后电流活性。因此，这些发现是有意义的，因为它们首次表明，GABAAR介导的兴奋作用可能对氯胺酮对发育中的大脑未成熟神经元的神经元兴奋毒性作用有明显贡献。