Gabapentin promotes inhibition by enhancing hyperpolarization-activated cation currents and spontaneous firing in hippocampal CA1 interneurons

The H-current (IH) regulates membrane electrical activity in many excitable cells. The antiepileptic drug gabapentin (GBP) has been shown to increase IH in hippocampal area CA1 pyramidal neurons, and this has been proposed as an anticonvulsant mechanism of action. IH also regulates excitability in some types of hippocampal interneuron that provide synaptic inhibition to CA1 pyramidal neurons, suggesting that global pharmacological IH enhancement could have more complex effects on the local synaptic network. However, whether IH in CA1 interneurons is modulated by GBP has not been examined. In this study, we tested the effects of GBP on IH on hippocampal area CA1 stratum oriens non-pyramidal neurons, and on spontaneous inhibitory postsynaptic currents (sIPSCs) in CA1 pyramidal neurons in immature rat brain slices. GBP (100 μM) increased IH in approximately 67% of interneurons that exhibited IH, with no apparent effect on cell types that did not exhibit IH. GBP also increased the frequency of spontaneous (but not miniature) inhibitory postsynaptic currents in pyramidal neurons without altering amplitudes or rise and decay times. These data indicate that IH in a subset of CA1 interneuron types can be increased by GBP, similarly to its effect on IH in pyramidal neurons, and further, that indirectly increased spontaneous inhibition of pyramidal neurons could contribute to its anticonvulsant effects.

► Gabapentin increased Ih in hippocampal interneurons.
► Gabapentin increased action potential firing in hippocampal pyramidal neurons.
► Gabapentin increased spontaneous inhibitory synaptic events in pyramidal neurons.
► Increasing in inhibition of principal neurons might be antiepileptic mechanism.