Ionic basis of neuronal hyperexcitability

本财政年度的工作继续集中在物理文献中的控制理论策略上，用于抑制神经元的节律性放电。起搏器神经元有一个所谓的“固定点”，通常接近-60毫伏，当细胞在电压箝位条件下保持在该电位时，净膜电流为零。电压钳法与抑制大脑兴奋性无关。我们在本实验室使用的模型准备（鱿鱼轴突和海蛸神经元）中抑制了兴奋性，采用一种称为动态钳的技术，实时监测电压波形，并将与电压成比例的电流信号延迟注入细胞。延迟的参考点是最近动作电位最大超调的时间。当延迟接近无扰动起搏器周期的中点并且反馈增益处于适当水平时，放电立即停止。细胞膜电位接近固定点，反馈电路注入的电流立即降为零，或接近于零。膜电位远离固定点，因为这一点是不稳定的，但反馈电路施加电流以防止它远离该点超过几mV。这是一种抑制超兴奋性的新机制，在这种机制中，一旦放电停止，只需要很少的电流。我们目前正在探索将这种方法应用于其他神经系统。

Work during the current fiscal year has continued to focus on a control theory strategy from the physics literature for suppressing rhythmic firing in neurons. Pacemaker neurons have what is known as a "fixed point", usually close to -60 mV where the net membrane current is zero when the cell is held at that potential in voltage clamp conditions. Voltage clamp methodology is not relevant for suppressing excitability in the brain. We have suppressed excitability in the model preparations used in this laboratory (squid axons and Aplysia neurons) with a technique known as a dynamic clamp in which the voltage waveform is monitored in real time and a current signal proportional to the voltage is injected back into the cell with a delay. The reference point for the delay is the time of the maximum overshoot of the most recent action potential. When the delay is near the midpoint of the unperturbed pacemaker cycle and the feedback gain is at the appropriate level, firing stops immediately. The cell membrane potential is close to its fixed point and so the current injected by the feedback circuit immediately drops to zero, or close to zero. The membrane potential moves away from the fixed point since this point is unstable, but the feedback circuit applies current to keep it from moving more than a few mV away from that point. This is a novel mechanism for suppressing hyperexcitability in which very little current is required once firing has ceased. We are currently exploring the use of this methodology for other neuronal systems.