Lee Kwan Young, Royston Sara E, Vest Max O, Ley Daniel J, Lee Seungbae, Bolton Eric C, Chung Hee Jung
Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, 407 South Goodwin Avenue, 524 Burrill Hall, Urbana, IL, 61801, USA.
Program in Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, Illinois, 61801, USA.
Mol Brain. 2015 Jan 20;8:4. doi: 10.1186/s13041-015-0094-1.
Homeostatic intrinsic plasticity encompasses the mechanisms by which neurons stabilize their excitability in response to prolonged and destabilizing changes in global activity. However, the milieu of molecular players responsible for these regulatory mechanisms is largely unknown.
Using whole-cell patch clamp recording and unbiased gene expression profiling in rat dissociated hippocampal neurons cultured at high density, we demonstrate here that chronic activity blockade induced by the sodium channel blocker tetrodotoxin leads to a homeostatic increase in action potential firing and down-regulation of potassium channel genes. In addition, chronic activity blockade reduces total potassium current, as well as protein expression and current of voltage-gated Kv1 and Kv7 potassium channels, which are critical regulators of action potential firing. Importantly, inhibition of N-Methyl-D-Aspartate receptors alone mimics the effects of tetrodotoxin, including the elevation in firing frequency and reduction of potassium channel gene expression and current driven by activity blockade, whereas inhibition of L-type voltage-gated calcium channels has no effect.
Collectively, our data suggest that homeostatic intrinsic plasticity induced by chronic activity blockade is accomplished in part by decreased calcium influx through N-Methyl-D-Aspartate receptors and subsequent transcriptional down-regulation of potassium channel genes.
稳态内在可塑性包含神经元在响应整体活动的长期不稳定变化时稳定其兴奋性的机制。然而，负责这些调节机制的分子参与者环境在很大程度上尚不清楚。
利用全细胞膜片钳记录和在高密度培养的大鼠海马解离神经元中进行的无偏基因表达谱分析，我们在此证明，钠通道阻滞剂河豚毒素诱导的慢性活动阻断导致动作电位发放的稳态增加和钾通道基因的下调。此外，慢性活动阻断会降低总钾电流，以及电压门控Kv1和Kv7钾通道的蛋白质表达和电流，这些通道是动作电位发放的关键调节因子。重要的是，单独抑制N-甲基-D-天冬氨酸受体可模拟河豚毒素的作用，包括发放频率升高以及由活动阻断驱动的钾通道基因表达和电流降低，而抑制L型电压门控钙通道则没有效果。
总体而言，我们的数据表明，慢性活动阻断诱导的稳态内在可塑性部分是通过N-甲基-D-天冬氨酸受体介导的钙内流减少以及随后钾通道基因的转录下调来实现的。
