Determination of effective synaptic conductances using somatic voltage clamp

The interplay between excitatory and inhibitory neurons imparts rich functions of the brain. To understand the synaptic mechanisms underlying neuronal computations, a fundamental approach is to study the dynamics of excitatory and inhibitory synaptic inputs of each neuron. The traditional method of determining input conductance, which has been applied for decades, employs the synaptic current-voltage (I-V) relation obtained via voltage clamp. Due to the space clamp effect, the measured conductance is different from the local conductance on the dendrites. Therefore, the interpretation of the measured conductance remains to be clarified. Using theoretical analysis, electrophysiological experiments, and realistic neuron simulations, here we demonstrate that there does not exist a transform between the local conductance and the conductance measured by the traditional method, due to the neglect of a nonlinear interaction between the clamp current and the synaptic current in the traditional method. Consequently, the conductance determined by the traditional method may not correlate with the local conductance on the dendrites, and its value could be unphysically negative as observed in experiment. To circumvent the challenge of the space clamp effect and elucidate synaptic impact on neuronal information processing, we propose the concept of effective conductance which is proportional to the local conductance on the dendrite and reflects directly the functional influence of synaptic inputs on somatic membrane potential dynamics, and we further develop a framework to determine the effective conductance accurately. Our work suggests re-examination of previous studies involving conductance measurement and provides a reliable approach to assess synaptic influence on neuronal computation.Author summary: To understand synaptic mechanisms underlying neuronal computations, a fundamental approach is to use voltage clamp to measure the dynamics of excitatory and inhibitory input conductances. Due to the space clamp effect, the measured conductance in general deviates from the local input conductance on the dendrites, hence its biological interpretation is questionable, as we demonstrate in this work. We further propose the concept of effective conductance that is proportional to the local input conductance on the dendrites and reflects directly the synaptic impact on spike generation, and develop a framework to determine the effective conductance reliably. Our work provides a biologically plausible metric for elucidating synaptic influence on neuronal computation under the constraint of the space clamp effect.