Cortical circuitry reconfigures in response to chronic (1-3 days) changes in activity levels. To understand this process, we must know the role played by inhibitory neurons since they greatly influence network properties by controlling action potential generation and synaptic integration. Using pharmacological blockade of activity in neocortical organotypic slice cultures, we examined the activity-dependent regulation of membrane excitability in a specific inhibitory neuron subtype: the somatostatin-positive (SOM+) neuron. Chronic action potential blockade (TTX, 2.5 days) resulted in increased excitability in SOM+ neurons. This result is consistent with a homeostatic process to maintain the average firing rate of SOM+ neurons at a particular level. Excitability changes were not due to changing cell size or alterations in voltage-dependent sodium current. Instead, the excitability increase was largely due to a decrease in the density of two subthreshold currents - a passive leak current (I_Leak) and H-current (I_H). The downregulation of these currents increased excitability mostly through a decrease in membrane input conductance. The co-adaptation of I_Leak and I_H enabled a change in input conductance while helping to preserve membrane potential. Evidence indicated that I_Leak was probably mainly mediated by K⁺. At earlier culture ages, this adaptation was superimposed on developmental changes, whereas at older ages, the same types of induced alterations occurred but with no developmental component. Together with other studies, these data indicate that both inhibitory and excitatory neurons increase membrane excitability with chronic reduction in activity, but through different mechanisms.