Numerical method for correcting the series resistance error in voltage clamp experiments

There is an inherent error in the voltage clamp, which is a major electrophysiological research tool. Current (I) flowing across the voltage-clamped membrane generates a drop in the resistance potential in series with the membrane (Rs) and thus an error in control of the potential. This error, which may be very significant, can only be partially corrected by electronic compensation during the experiment. Subsequent correction by computation is generally believed impossible for membrane potentials (Vm) for which the conductance parameters are voltage dependent. In the proposed method, which is based on the assumption that dI/dt is a function of I and Vm only, the reconstruction begins with very small sodium or potassium currents (for which the Rs error is negligible). The subsequent I value is calculated using a dI/dt value obtained under any set of conditions where Vm is known to have the desired value (as ensured by the experimental protocol) and where I equals the initial I value. By iterations, the correct I vs. t curve is reconstructed for the chosen potential. It is shown analytically that for squid giant axons, with an uncompensated Rs of 5 omega . cm2 the maximal error in INa is reduced from about 30% to under 3%. The validity of the reconstruction is demonstrated experimentally by corrected INa generated in artificial seawater and comparing it with INa obtained in a solution containing a low concentration of tetrodotoxin.