Ionic basis of neuronal hyperexcitability

National Institute Of Neurological Disorders And Stroke

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Abstract

The most significant accomplishment of this project during the current fiscal year has been the implementation of a control theory strategy from the physics literature for suppressing rhythmic firing in alkalinized squid giant axons. Squid axons are robust pacemaker cells firing at 25 Hz for hours on end when the intracellular pH is elevated to 7.8, or higher. They do have what is known as a "fixed point" at -55 mV where the net membrane current is zero when the cell is held at that potential in voltage clamp conditions. However, voltage clamp methodology is not relevant to deep brain stimulation. Moreover, the fixed point is unstable. Rhythmic firing resumes immediately after the voltage clamp is turned off. We have suppressed firing with a technique knows 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 at the 60% point of the unperturbed pacemaker cycle and the feedback gain is at the appropriate level, firing stops immediately. The cell 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 mechanism for suppressing hyperexcitability in which very little current is required once firing has ceased. A flat baseline can never be achieved, but firing of action potentials is eliminated. We are currently investigating the relevance of these results for deep brain stimulation methodologies.