Ionic basis of neuronal hyperexcitability

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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.