Abstracts

The anticonvulsant mechanism of gabapentin (Neurontin[reg]) has yet to be fully elucidated. Gabapentin increases the hyperpolarization-activated cation current (I[sub]H[/sub]) in hippocampal CA1 pyramidal neurons (Surges, et al., 2003 Epilepsia 44:150), and I[sub]H[/sub] enhancement in these cells has been proposed to decrease passive conduction of dendritic excitatory postsynaptic potentials (dampening synaptic excitability) by decreasing dendritic membrane resistance (Poolos, et al., 2002 Nat Neurosci 5:767). Notably, I[sub]H[/sub] also is expressed in hippocampal inhibitory interneurons, and I[sub]H[/sub] blockade in hippocampal slices was shown to decrease spontaneous inhibitory postsynaptic current (sIPSC) frequency in CA1 pyramidal neurons (Lupica, et al., 2001 J Neurophysiol 86:261). This suggested that I[sub]H[/sub] activation normally promotes the spontaneous firing of CA1 inhibitory interneurons, perhaps in contrast to its effects on pyramidal neuron excitability. We aimed to determine if, as in pyramidal cells, gabapentin increases I[sub]H[/sub] in non-pyramidal CA1 interneurons, and whether this effect is associated with increased sIPSC frequency in CA1 pyramidal neurons. Whole-cell voltage-clamp recordings were obtained from visualized CA1 pyramidal neurons and CA1 s. oriens non-pyramidal neurons in hippocampal slices from P10-17 Long-Evans rat pups. The effects of bath-applied gabapentin (100 [mu]M) and the I[sub]H[/sub] blocker ZD 7288 (50 [mu]M) were examined on I[sub]H[/sub] recorded from s. oriens interneurons and on sIPSC parameters in pyramidal neurons. I[sub]H[/sub] was observed in 91% (10/11) of recorded CA1 s. oriens interneurons. Gabapentin significantly increased I[sub]H[/sub] in 7 of 10 interneurons that expressed I[sub]H[/sub] within 5-10 minutes of bath application. Analysis of tail-currents indicated that the voltage-dependence of I[sub]H[/sub] activation was unaltered by the drug. Subsequent application of ZD 7288 completely blocked I[sub]H[/sub] in all interneurons tested (7/7) regardless of whether prior gabapentin application had increased I[sub]H[/sub]. In CA1 pyramidal neurons, gabapentin significantly increased sIPSC frequencies within 5-10 minutes in 69% (11/16) of cells. ZD 7288 signficantly decreased sIPSC frequency in all cells tested (n=7), and also prevented any change by subsequent combined application of gabapentin and ZD 7288. sIPSC amplitudes and rise times were not altered by either drug. These data indicate that gabapentin can increase I[sub]H[/sub] in CA1 hippocampal interneurons, similarly to its action in CA1 pyramidal neurons. However, rather than decreasing interneuron excitability, this effect is associated with an increase in spontaneous firing of interneurons, as indicated by increased sIPSC frequency in pyramidal neurons. This increase in basal synaptic inhibition may represent a mechanism by which gabapentin decreases pyramidal neuron synaptic excitability, in addition to its possible direct dampening of dendritic synaptic excitation. (Supported by PHS grant NS 047385 and an EFA Junior Investigator Award.)