Abstract
The voltage clamp technique is frequently used to examine the strength and composition of synaptic input to neurons. Even accounting for imperfect voltage control of the entire cell membrane (“space clamp”), it is often assumed that currents measured at the soma are a proportional indicator of the postsynaptic conductance. Here, using NEURON simulation software to model somatic recordings from morphologically realistic neurons, we show that excitatory conductances recorded in voltage clamp mode are distorted significantly by neighboring inhibitory conductances, even when the postsynaptic membrane potential starts at the reversal potential of the inhibitory conductance. Analogous effects are observed when inhibitory postsynaptic currents are recorded at the reversal potential of the excitatory conductance. Escape potentials in poorly clamped dendrites reduce the amplitude of excitatory or inhibitory postsynaptic currents recorded at the reversal potential of the other conductance. In addition, unclamped postsynaptic inhibitory conductances linearize the recorded current-voltage relationship of excitatory inputs comprising AMPAR and NMDAR-mediated components, leading to significant underestimation of the relative contribution by NMDARs, which are particularly sensitive to small perturbations in membrane potential. Voltage clamp accuracy varies substantially between neurons and dendritic arbors of different morphology; as expected, more reliable recordings are obtained from dendrites near the soma, but up to 80% of the synaptic signal on thin, distant dendrites may be lost when postsynaptic interactions are present. These limitations of the voltage clamp technique may explain how postsynaptic effects on synaptic transmission could, in some cases, be attributed incorrectly to presynaptic mechanisms.
Highlights
Most neurons receive myriad excitatory and inhibitory synaptic inputs in complex spatial-temporal patterns
Space clamp errors influence voltage clamp recordings Our initial simulations were performed on a schematic model of a neuron shown in Fig. 1 A
The soma of the simulated cell was voltage clamped and we examined the reliability of the Reversal Potential Clamp (RPC) technique
Summary
Most neurons receive myriad excitatory and inhibitory synaptic inputs in complex spatial-temporal patterns. The dynamic balance between excitation and inhibition (E/I) is important in determining neural activity, but is hard to detect directly. Among a number of indirect techniques used to detect synaptic composition, one of the most popular is the somatic single electrode voltage clamp, which has been applied in a wide variety of in-vivo and in-vitro preparations. The E/I balance can be calculated from recorded currents with a number of different methods. The first technique assumes that, when the cell is clamped at either the excitatory or the inhibitory reversal potential, the respective synaptic drive is neutralized and doesn’t contribute to the recorded current at the electrode. By recording sequentially excitatory and inhibitory currents it is presumably possible to determine whether the E/I balance changes between different conditions [1,2,3,4]
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