Cholanian Marina, Wealing Jesse, Levine Richard B, Fregosi Ralph F
Department of Physiology, The University of Arizona, Tucson, Arizona.
Department of Environmental and Evolutionary Biology, The University of Arizona, Tucson, Arizona; and.
J Neurophysiol. 2017 Apr 1;117(4):1544-1552. doi: 10.1152/jn.00774.2016. Epub 2017 Feb 1.
We previously showed that nicotine exposure in utero and after birth via breast milk [developmental nicotine exposure (DNE)] is associated with many changes in the structure and function of hypoglossal motoneurons (XIIMNs), including a reduction in the size of the dendritic arbor and an increase in cell excitability. Interestingly, the elevated excitability was associated with a reduction in the expression of glutamate receptors on the cell body. Together, these observations are consistent with a homeostatic compensation aimed at restoring cell excitability. Compensation for increased cell excitability could also occur by changing potassium conductance, which plays a critical role in regulating resting potential, spike threshold, and repetitive spiking behavior. Here we test the hypothesis that the previously observed increase in the excitability of XIIMNs from DNE animals is associated with an increase in whole cell potassium currents. Potassium currents were measured in XIIMNs in brain stem slices derived from DNE and control rat pups ranging in age from 0 to 4 days by whole cell patch-clamp electrophysiology. All currents were measured after blockade of action potential-dependent synaptic transmission with tetrodotoxin. Compared with control cells, XIIMNs from DNE animals showed significantly larger transient and sustained potassium currents, but this was observed only under conditions of increased cell and network excitability, which we evoked by raising extracellular potassium from 3 to 9 mM. These observations suggest that the larger potassium currents in nicotine-exposed neurons are an important homeostatic compensation that prevents "runaway" excitability under stressful conditions, when neurons are receiving elevated excitatory synaptic input. Developmental nicotine exposure is associated with increased cell excitability, which is often accompanied by compensatory changes aimed at normalizing excitability. Here we show that whole cell potassium currents are also increased in hypoglossal motoneurons from nicotine-exposed neonatal rats under conditions of increased cell and network excitability. This is consistent with a compensatory response aimed at preventing instability under conditions in which excitatory synaptic input is high and is compatible with the concept of homeostatic plasticity.
我们之前的研究表明，子宫内及出生后通过母乳接触尼古丁（发育性尼古丁暴露，DNE）与舌下运动神经元（XIIMNs）的结构和功能发生多种变化有关，包括树突分支大小减小以及细胞兴奋性增加。有趣的是，兴奋性升高与细胞体上谷氨酸受体表达减少有关。这些观察结果共同表明存在一种旨在恢复细胞兴奋性的稳态补偿机制。细胞兴奋性增加的补偿也可能通过改变钾电导来实现，钾电导在调节静息电位、动作电位阈值和重复放电行为中起关键作用。在此，我们检验这样一个假设，即先前观察到的来自DNE动物的XIIMNs兴奋性增加与全细胞钾电流增加有关。通过全细胞膜片钳电生理学方法，在年龄为0至4天的DNE和对照大鼠幼崽的脑干切片中的XIIMNs中测量钾电流。在用河豚毒素阻断依赖动作电位的突触传递后测量所有电流。与对照细胞相比，来自DNE动物的XIIMNs表现出明显更大的瞬时和持续钾电流，但这仅在我们通过将细胞外钾从3 mM提高到9 mM所诱发的细胞和网络兴奋性增加的条件下观察到。这些观察结果表明，尼古丁暴露神经元中较大的钾电流是一种重要的稳态补偿机制，可在应激条件下（即神经元接受增强的兴奋性突触输入时）防止“失控”的兴奋性。发育性尼古丁暴露与细胞兴奋性增加有关，这通常伴随着旨在使兴奋性正常化的补偿性变化。在此我们表明，在细胞和网络兴奋性增加的条件下，来自尼古丁暴露新生大鼠的舌下运动神经元中的全细胞钾电流也会增加。这与旨在防止在兴奋性突触输入较高的条件下出现不稳定的补偿反应一致，并且与稳态可塑性的概念相符。
