Increased Basal Synaptic Inhibition of Hippocampal Area CA1 Pyramidal Neurons by an Antiepileptic Drug that Enhances IH

Abstract

The hyperpolarization-activated cation current IH regulates the electrical activity of many excitable cells, but its precise function varies across cell types. The antiepileptic drug lamotrigine (LTG) recently was shown to enhance IH in hippocampal CA1 pyramidal neurons, revealing a potential anticonvulsant mechanism, as IH can dampen dendrito-somatic propagation of excitatory postsynaptic potentials in these cells. However, IH also is expressed in many hippocampal interneurons that provide synaptic inhibition to CA1 pyramidal neurons, and thus, IH modulation may indirectly regulate inhibitory control of principal cells via direct modulation of interneuron activity. Whether IH in hippocampal interneurons is sensitive to modulation by LTG, and how this may affect synaptic inhibition of pyramidal cells has not been investigated. In this study, we examined the effects of LTG on IH and spontaneous firing of area CA1 s.o. interneurons, and on spontaneous inhibitory postsynaptic currents (sIPSCs) in CA1 pyramidal neurons in immature rat brain slices. LTG (100 µM) significantly increased IH in the majority of interneurons, and depolarized interneurons from rest, promoting spontaneous firing. LTG also caused an increase in the frequency of spontaneous (but not miniature) IPSCs in pyramidal neurons without significantly altering amplitudes or rise and decay times. These data indicate that IH in CA1 interneurons can be increased by LTG, similarly to IH in pyramidal neurons, that IH enhancement increases interneuron excitability, and that these effects are associated with increased basal synaptic inhibition of CA1 pyramidal neurons.

Recessive Loss-of-Function Mutation in the Pacemaker HCN2 Channel Causing Increased Neuronal Excitability in a Patient with Idiopathic Generalized Epilepsy

“…Several studies suggest that downregulation of I h can be proepileptogenic (Peng et al, 2010). In a rat chemoconvulsant (pilocarpine) model of epilepsy, dendritic HCN channels of CA1 hippocampal neurons were substantially downregulated (Jung et al, 2007); interestingly, the activation curve of I h recorded from postpilocarpine CA1 pyramidal neuron dendrites was more negative than in sham animals, similar to the effect we have observed with E515K channels (Figs.…”

“…The antiepileptic drug lamotrigine (LTG) increases I h in hippocampal CA1 pyramidal neurons by a depolarizing shift of the I h activation curve (Poolos et al, 2002) and/or increased I h conductance (Peng et al, 2010). This action of LTG leads to a depression of dendritic synaptic excitability (Poolos et al, 2002), supporting the view that the opposite action, i.e., I h downregulation, underlies amplification of EPSP summation and hyperexcitability.…”

“…It should be noted that opposite results have also been reported, such as upregulation of I h in hyperexcitable CA1 pyramidal neurons following febrile seizures (Chen et al, 2001;Dyhrfjeld-Johnsen et al, 2009). I h may therefore be antiepileptogenic in some settings when enhanced, and in others when depressed (Peng et al, 2010). This dichotomy likely results from the balance between the contrasting effects on input resistance and membrane resting voltage level, which may vary as a function of neuron type, developmental stage, distribution of channel expression, channel modulation, and other factors (DyhrfjeldJohnsen et al, 2009;Noam and Baram, 2010).…”

Dysfunction of hippocampal interneurons in epilepsy

“…In a recent study, topiramate was shown to reduce the hyperexcitability in the basolateral amygdala by selectively inhibiting GluK1 (GluR5) kainate receptors on interneurons, enhancing GABAergic transmission in interneuron-to-pyramidal cell synapses, and directly enhancing GABA A receptor-mediated inhibitory currents [78] . In addition, Peng et al [79,80] concluded that the AEDs gabapentin and lamotrigine increase the hyperpolarization-activated cation current (I-H) in CA1 interneurons by decreasing EPSC frequency or increasing IPSC frequency, similar to I-H in pyramidal neurons and I-H enhancement-increased interneuron excitability. Thus, these drugs indirectly increase the spontaneous inhibition of pyramidal neurons.…”

Decreased hyperpolarization-activated currents in layer 5 pyramidal neurons enhances excitability in focal cortical dysplasia

“…Anticonvulsant drugs such as lamotrigine (Peng et al 2010;Poolos et al 2002) and gabapentin (Surges et al 2003) have been shown to enhance I h . The effect of enhancing I h on network behavior has received little attention.…”