Frequency-dependent responses of neuronal models to oscillatory inputs in current versus voltage clamp

Action potential generation in neurons depends on a membrane potential threshold and therefore on how subthreshold inputs influence this voltage. In oscillatory networks, for example, many neuron types have been shown to produce membrane potential ([Formula: see text]) resonance: a maximum subthreshold response to oscillatory inputs at a nonzero frequency. Resonance is usually measured by recording [Formula: see text] in response to a sinusoidal current ([Formula: see text]), applied at different frequencies (f), an experimental setting known as current clamp (I-clamp). Several recent studies, however, use the voltage clamp (V-clamp) method to control [Formula: see text] with a sinusoidal input at different frequencies [[Formula: see text]] and measure the total membrane current ([Formula: see text]). The two methods obey systems of differential equations of different dimensionality, and while I-clamp provides a measure of electrical impedance [[Formula: see text]], V-clamp measures admittance [[Formula: see text]]. We analyze the relationship between these two measurement techniques. We show that, despite different dimensionality, in linear systems the two measures are equivalent: [Formula: see text]. However, nonlinear model neurons produce different values for Z and [Formula: see text]. In particular, nonlinearities in the voltage equation produce a much larger difference between these two quantities than those in equations of recovery variables that describe activation and inactivation kinetics. Neurons are inherently nonlinear, and notably, with ionic currents that amplify resonance, the voltage clamp technique severely underestimates the current clamp response. We demonstrate this difference experimentally using the PD neurons in the crab stomatogastric ganglion. These findings are instructive for researchers who explore cellular mechanisms of neuronal oscillations.