Computer simulations of voltage-clamp experiments in retinal ganglion cells were implemented to better understand the insights that can be obtained with this physiological approach. 2. Simulation studies of voltage clamping were based on the contemporary approach of using whole-cell recordings with low resistance electrodes attached to the soma. Realistic ganglion cell morphologies were provided by cell staining experiments in the mudpuppy retina; selected cells included small-, medium-, and large-field neurons whose morphologies were entered into a computer through a neuron tracing program. 3. Values for the specific membrane resistance (Rm) varied from 5,000 to 100,000 omega/cm2 to conform to the range of Rm values obtained with intracellular sharp electrodes and whole-cell recordings. 4. Synaptic input currents were simulated by injecting current with and without an underlying conductance change into different regions of the dendritic tree. The time-variant waveform of the current included a combined transient and sustained component similar to the waveform of ON-bipolar activation. 5. Simulations were base on 1) intact structures, which included the soma and the entire dendritic tree, and 2) a more limited cell geometry that included representation of the soma, but only part of the dendritic tree, to represent the restricted morphology that might be rendered after cutting the retina into 150-microns cross sections for retinal slice experiments. 6. The results of this study indicate that voltage clamping from the soma, with optimal, low resistance electrodes and series resistance compensation, provides an error-free voltage clamp for slow signals that are generated within a small electrotonic distance from the soma (approximately 0.1 lambda). 7. The ideal voltage-clamp conditions are optimized when synaptic conductances are small and nonlinear membrane elements are minimally activated: small-field neurons best approximate these conditions, but clamping errors are evident in these cells when more distal branches are activated. The degree of error in voltage clamping was much greater when medium-and large-field neurons were evaluated. 8. It was not possible to clamp action potentials (nonpropagating) even when they were generated near the soma in any of the three model cells examined. 9. Experimental paradigms were developed to demonstrate that inadequate voltage clamping can lead to errors in the interpretation of experimental data when relevant variables are not taken into consideration. Suggestions are made for determining and optimizing favorable clamp conditions.
