Though the precise mechanisms of gain modulation in the cortex still need to be elucidated, several theoretical models and some experimental observations indicate that synaptic inhibition is likely to play a key role. Curiously, adding a tonic inhibitory conductance to a neuron does not affect the gain of the neuron's input-output relationship, if the driving input is a simple depolarizing current step. This may seem counterintuitive but experimental manipulations clearly indicate that decreasing the resistance of a neuron (as happens when adding an inhibitory conductance) does not change the slope of the input-output relationship to depolarizing current steps (Chance et al., 2002; Mitchell and Silver, 2003). Furthermore neuronal models provide a theoretical framework for these observations (Holt and Koch, 1997). However, under physiological conditions, neuronal spike output is driven by the integration of barrages of synaptic inputs rather than depolarizing current steps and voltage noise from transient synaptic conductances contributes to the frequency of spike output. If the opening of a tonic inhibitory conductance occurs in combination with an increase in the variability of driving excitatory input (Mitchell and Silver,
