Chrna2‐OLM interneurons display different membrane properties and h‐current magnitude depending on dorsoventral location

The hippocampus is an extended structure displaying heterogeneous anatomical cell layers along its dorsoventral axis. It is known that dorsal and ventral regions show different integrity when it comes to functionality, innervation, gene expression, and pyramidal cell properties. Still, whether hippocampal interneurons exhibit different properties along the dorsoventral axis is not known. Here, we report electrophysiological properties of dorsal and ventral oriens lacunosum moleculare (OLM) cells from coronal sections of the Chrna2‐cre mouse line. We found dorsal OLM cells to exhibit a significantly more depolarized resting membrane potential compared to ventral OLM cells, while action potential properties were similar between the two groups. We found ventral OLM cells to show a higher initial firing frequency in response to depolarizing current injections but also to exhibit a higher spike‐frequency adaptation than dorsal OLM cells. Additionally, dorsal OLM cells displayed large membrane sags in response to negative current injections correlating with our results showing that dorsal OLM cells have more hyperpolarization‐activated current (I_h) compared to ventral OLM cells. Immunohistochemical examination indicates the h‐current to correspond to hyperpolarization‐activated cyclic nucleotide‐gated subunit 2 (HCN2) channels. Computational studies suggest that I_h in OLM cells is essential for theta oscillations in hippocampal circuits, and here we found dorsal OLM cells to present a higher membrane resonance frequency than ventral OLM cells. Thus, our results highlight regional differences in membrane properties between dorsal and ventral OLM cells allowing this interneuron to differently participate in the generation of hippocampal theta rhythms depending on spatial location along the dorsoventral axis of the hippocampus.     

Long‐term high‐intensity sound stimulation inhibits h current (Ih) in CA1 pyramidal neurons

Afferent neurotransmission to hippocampal pyramidal cells can lead to long‐term changes to their intrinsic membrane properties and affect many ion currents. One of the most plastic neuronal currents is the hyperpolarization‐activated cationic current (I_h), which changes in CA1 pyramidal cells in response to many types of physiological and pathological processes, including auditory stimulation. Recently, we demonstrated that long‐term potentiation (LTP) in rat hippocampal Schaffer‐CA1 synapses is depressed by high‐intensity sound stimulation. Here, we investigated whether a long‐term high‐intensity sound stimulation could affect intrinsic membrane properties of rat CA1 pyramidal neurons. Our results showed that I_h is depressed by long‐term high‐intensity sound exposure (1 min of 110 dB sound, applied two times per day for 10 days). This resulted in a decreased resting membrane potential, increased membrane input resistance and time constant, and decreased action potential threshold. In addition, CA1 pyramidal neurons from sound‐exposed animals fired more action potentials than neurons from control animals; however, this effect was not caused by a decreased I_h. On the other hand, a single episode (1 min) of 110 dB sound stimulation which also inhibits hippocampal LTP did not affect I_h and firing in pyramidal neurons, suggesting that effects on I_h are long‐term responses to high‐intensity sound exposure. Our results show that prolonged exposure to high‐intensity sound affects intrinsic membrane properties of hippocampal pyramidal neurons, mainly by decreasing the amplitude of I_h.     

Ih “run‐up” in rat neocortical neurons and transiently rat or human HCN1‐expressing HEK293 cells

Hyperpolarization‐activated cyclic nucleotide‐gated ion channels (HCN) are key determinants of CNS functions. Here we describe an increase in hyperpolarization‐activated current (I_h) at the beginning of whole‐cell recordings in rat layer 5 cortical neurons. For a closer investigation of this I_h increase, we overexpressed the predominant layer 5 rat subunit HCN1 in HEK293 cells. We characterized the resulting I_h in the cell‐attached and whole‐cell configurations. Breaking into whole‐cell configuration led to about a 30% enhancement of rat HCN1‐mediated I_h accompanied by a depolarizing shift in voltage dependence and an accelerated time course of activation. This current enhancement is not species specific; for human HCN1, the current similarly increases in amount and kinetics. Although the changes were bound to cytosolic solution exchange, they were independent of cAMP, ATP, GTP, and the phosphate group donor phosphocreatine. Together, these data provide a characterization of heterologous expression of rat HCN1 and suggest that cytosolic contents suppress I_h. Such a mechanism might constitute a reserve in h‐channel function in vivo. © 2010 Wiley‐Liss, Inc.     

h-Ströme in epilepsiechirurgischen Resektaten

In recent years ion channels of the hyperpolarization activated cyclic nucleotide gated (HCN) channels type have attracted considerable attention. These channels have some unusual properties, one of which is the activation by hyperpolarization. The h-current that is mediated by the HCN channels crucially determines the excitability of neurons and reduction of this current has been demonstrated in various animal models of epilepsy. Possible alterations in human temporal lobe epilepsy (TLE) have been sparsely investigated. In the study the properties of h-currents were investigated in neocortical neurons from tissue removed by epilepsy surgery with patch-clamp recording. In comparison to rats the h-currents in TLE tissues were 63?% lower and activate more slowly. In tissue from patients who suffered many seizures the current was decreased by approximately ?24?% compared to tissue from patients who suffered few seizures. In comparison to autopsy controls the expression (mRNA) of subunits was altered in TLE tissues with an approximately 53?% decrease of HCN1 and a ?153?% increase of HCN4. The altered expression of subunits might contribute to the reduction and slowed activation of h-currents and might thus facilitate the spread of seizure activity in the human neocortex.     

Transient cerebral ischemia increases CA1 pyramidal neuron excitability

In human and experimental animals, the hippocampal CA1 region is one of the most vulnerable areas of the brain to ischemia. Pyramidal neurons in this region die 2–3 days after transient cerebral ischemia whereas other neurons in the same region remain intact. The mechanisms underlying the selective and delayed neuronal death are unclear. We tested the hypothesis that there is an increase in post-synaptic intrinsic excitability of CA1 pyramidal neurons after ischemia that exacerbates glutamatergic excitotoxicity. We performed whole-cell patch-clamp recordings in brain slices obtained 24 h after in vivo transient cerebral ischemia. We found that the input resistance and membrane time constant of the CA1 pyramidal neurons were significantly increased after ischemia, indicating an increase in neuronal excitability. This increase was associated with a decrease in voltage sag, suggesting a reduction of the hyperpolarization-activated non-selective cationic current (I_h). Moreover, after blocking I_h with ZD7288, the input resistance of the control neurons increased to that of the post-ischemia neurons, suggesting that a decrease in I_h contributes to increased excitability after ischemia. Finally, when lamotrigine, an enhancer of dendritic I_h, was applied immediately after ischemia, there was a significant attenuation of CA1 cell loss. These data suggest that an increase in CA1 pyramidal neuron excitability after ischemia may exacerbate cell loss. Moreover, this dendritic channelopathy may be amenable to treatment.     

The CAN‐In network: A biologically inspired model for self‐sustained theta oscillations and memory maintenance in the hippocampus

During working memory tasks, the hippocampus exhibits synchronous theta‐band activity, which is thought to be correlated with the short‐term memory maintenance of salient stimuli. Recent studies indicate that the hippocampus contains the necessary circuitry allowing it to generate and sustain theta oscillations without the need of extrinsic drive. However, the cellular and network mechanisms supporting synchronous rhythmic activity are far from being fully understood. Based on electrophysiological recordings from hippocampal pyramidal CA1 cells, we present a possible mechanism for the maintenance of such rhythmic theta‐band activity in the isolated hippocampus. Our model network, based on the Hodgkin‐Huxley formalism, comprising pyramidal neurons equipped with calcium‐activated nonspecific cationic (CAN) ion channels, is able to generate and sustain synchronized theta oscillations (4–12 Hz), following a transient stimulation. The synchronous network activity is maintained by an intrinsic CAN current (I_CAN), in the absence of constant external input. When connecting the pyramidal‐CAN network to fast‐spiking inhibitory interneurons, the dynamics of the model reveal that feedback inhibition improves the robustness of fast theta oscillations, by tightening the synchronization of the pyramidal CAN neurons. The frequency and power of the theta oscillations are both modulated by the intensity of the I_CAN, which allows for a wide range of oscillation rates within the theta band. This biologically plausible mechanism for the maintenance of synchronous theta oscillations in the hippocampus aims at extending the traditional models of septum‐driven hippocampal rhythmic activity. © 2017 Wiley Periodicals, Inc.     

Intrahippocampal infusion of the Ih blocker ZD7288 slows evoked theta rhythm and produces anxiolytic‐like effects in the elevated plus maze

Hippocampal theta rhythm has been associated with a number of behavioral processes, including learning and memory, spatial behavior, sensorimotor integration and affective responses. Suppression of hippocampal theta frequency has been shown to be a reliable neurophysiological signature of anxiolytic drug action in tests using known anxiolytic drugs (i.e., correlational evidence), but only one study to date (Yeung et al. ( 2012 ) Neuropharmacology 62:155–160) has shown that a drug with no known effect on either hippocampal theta or anxiety can in fact separately suppress hippocampal theta and anxiety in behavioral tests (i.e., prima facie evidence). Here, we attempt a further critical test of the hippocampal theta model by performing intrahippocampal administrations of the I_h blocker ZD7288, which is known to disrupt theta frequency subthreshold oscillations and resonance at the membrane level but is not known to have anxiolytic action. Intrahippocampal microinfusions of ZD7288 at high (15 µg), but not low (1 µg) doses slowed brainstem‐evoked hippocampal theta responses in the urethane anesthetized rat, and more importantly, promoted anxiolytic action in freely behaving rats in the elevated plus maze. Taken together with our previous demonstration, these data provide converging, prima facie evidence of the validity of the theta suppression model. © 2012 Wiley Periodicals, Inc.     

Postnatal development of temporal integration,spike timing and spike threshold regulation by a dendrotoxin‐sensitive K+ current in rat CA1 hippocampal cells

Spike timing and network synchronization are important for plasticity, development and maturation of brain circuits. Spike delays and timing can be strongly modulated by a low‐threshold, slowly inactivating, voltage‐gated potassium current called D‐current (I_D). I_D can delay the onset of spiking, cause temporal integration of multiple inputs, and regulate spike threshold and network synchrony. Recent data indicate that I_D can also undergo activity‐dependent, homeostatic regulation. Therefore, we have studied the postnatal development of I_D‐dependent mechanisms in CA1 pyramidal cells in hippocampal slices from young rats (P7–27), using somatic whole‐cell recordings. At P21–27, these neurons showed long spike delays and pronounced temporal integration in response to a series of brief depolarizing current pulses or a single long pulse, whereas younger cells (P7–20) showed shorter discharge delays and weak temporal integration, although the spike threshold became increasingly negative with maturation. Application of α‐dendrotoxin (α‐DTX), which blocks I_D, reduced the spiking latency and temporal integration most strongly in mature cells, while shifting the spike threshold most strongly in a depolarizing direction in these cells. Voltage‐clamp analysis revealed an α‐DTX‐sensitive outward current (I_D) that increased in amplitude during development. In contrast to P21–23, I_D in the youngest group (P7–9) showed smaller peri‐threshold amplitude. This may explain why long discharge delays and robust temporal integration only appear later, 3 weeks postnatally. We conclude that I_D properties and I_D‐dependent functions develop postnatally in rat CA1 pyramidal cells, and I_D may modulate network activity and plasticity through its effects on synaptic integration, spike threshold, timing and synchrony.     

GABAergic contributions to gating,timing, and phase precession of hippocampal neuronal activity during theta oscillations

Successful spatial exploration requires gating, storage, and retrieval of spatial memories in the correct order. The hippocampus is known to play an important role in the temporal organization of spatial information. Temporally ordered spatial memories are encoded and retrieved by the firing rate and phase of hippocampal pyramidal cells and inhibitory interneurons with respect to ongoing network theta oscillations paced by intra‐ and extrahippocampal areas. Much is known about the anatomical, physiological, and molecular characteristics as well as the connectivity and synaptic properties of various cell types in the hippocampal microcircuits, but how these detailed properties of individual neurons give rise to temporal organization of spatial memories remains unclear. We present a model of the hippocampal CA1 microcircuit based on observed biophysical properties of pyramidal cells and six types of inhibitory interneurons: axo‐axonic, basket, bistratistified, neurogliaform, ivy, and oriens lacunosum‐moleculare cells. The model simulates a virtual rat running on a linear track. Excitatory transient inputs come from the entorhinal cortex (EC) and the CA3 Schaffer collaterals and impinge on both the pyramidal cells and inhibitory interneurons, whereas inhibitory inputs from the medial septum impinge only on the inhibitory interneurons. Dopamine operates as a gate‐keeper modulating the spatial memory flow to the PC distal dendrites in a frequency‐dependent manner. A mechanism for spike‐timing‐dependent plasticity in distal and proximal PC dendrites consisting of three calcium detectors, which responds to the instantaneous calcium level and its time course in the dendrite, is used to model the plasticity effects. The model simulates the timing of firing of different hippocampal cell types relative to theta oscillations, and proposes functional roles for the different classes of the hippocampal and septal inhibitory interneurons in the correct ordering of spatial memories as well as in the generation and maintenance of theta phase precession of pyramidal cells (place cells) in CA1. The model leads to a number of experimentally testable predictions that may lead to a better understanding of the biophysical computations in the hippocampus and medial septum. © 2012 Wiley Periodicals, Inc.     

Human cerebrospinal fluid promotes spontaneous gamma oscillations in the hippocampus in vitro

Gamma oscillations (30–80 Hz) are fast network activity patterns frequently linked to cognition. They are commonly studied in hippocampal brain slices in vitro, where they can be evoked via pharmacological activation of various receptor families. One limitation of this approach is that neuronal activity is studied in a highly artificial extracellular fluid environment, as provided by artificial cerebrospinal fluid (aCSF). Here, we examine the influence of human cerebrospinal fluid (hCSF) on kainate‐evoked and spontaneous gamma oscillations in mouse hippocampus. We show that hCSF, as compared to aCSF of matched electrolyte and glucose composition, increases the power of kainate‐evoked gamma oscillations and induces spontaneous gamma activity in areas CA3 and CA1 that is reversed by washout. Bath application of atropine entirely abolished hCSF‐induced gamma oscillations, indicating critical contribution from muscarinic acetylcholine receptor‐mediated signaling. In separate whole‐cell patch clamp recordings from rat hippocampus, hCSF increased theta resonance frequency and strength in pyramidal cells along with enhancement of h‐current (I_h) amplitude. We found no evidence of intrinsic gamma frequency resonance at baseline (aCSF) among fast‐spiking interneurons, and this was not altered by hCSF. However, hCSF increased the excitability of fast‐spiking interneurons, which likely contributed to gamma rhythmogenesis. Our findings show that hCSF promotes network gamma oscillations in the hippocampus in vitro and suggest that neuromodulators distributed in CSF could have significant influence on neuronal network activity in vivo.     

The hyperpolarization‐activated non‐specific cation current (Ih) adjusts the membrane properties,excitability, and activity pattern of the giant cells in the rat dorsal cochlear nucleus

Giant cells of the cochlear nucleus are thought to integrate multimodal sensory inputs and participate in monaural sound source localization. Our aim was to explore the significance of a hyperpolarization‐activated current in determining the activity of giant neurones in slices prepared from 10 to 14‐day‐old rats. When subjected to hyperpolarizing stimuli, giant cells produced a 4‐(N‐ethyl‐N‐phenylamino)‐1,2‐dimethyl‐6‐(methylamino) pyridinium chloride (ZD7288)‐sensitive inward current with a reversal potential and half‐activation voltage of –36 and –88 mV, respectively. Consequently, the current was identified as the hyperpolarization‐activated non‐specific cationic current (I_h). At the resting membrane potential, 3.5% of the maximum I_h conductance was available. Immunohistochemistry experiments suggested that hyperpolarization‐activated, cyclic nucleotide‐gated, cation non‐selective (HCN)1, HCN2, and HCN4 subunits contribute to the assembly of the functional channels. Inhibition of I_h hyperpolarized the membrane by 6 mV and impeded spontaneous firing. The frequencies of spontaneous inhibitory and excitatory postsynaptic currents reaching the giant cell bodies were reduced but no significant change was observed when evoked postsynaptic currents were recorded. Giant cells are affected by biphasic postsynaptic currents consisting of an excitatory and a subsequent inhibitory component. Inhibition of I_h reduced the frequency of these biphasic events by 65% and increased the decay time constants of the inhibitory component. We conclude that I_h adjusts the resting membrane potential, contributes to spontaneous action potential firing, and may participate in the dendritic integration of the synaptic inputs of the giant neurones. Because its amplitude was higher in young than in adult rats, I_h of the giant cells may be especially important during the postnatal maturation of the auditory system.     

Metabolic and pathological effects of temporal lobe epilepsy in rat brain detected by proton spectroscopy and imaging

The goal of these experiments was to test the hypothesis that in an animal model of temporal lobe epilepsy (TLE), magnetic resonance spectroscopic measurement of N-acetylaspartate (NAA) and other metabolites, together with magnetic resonance imaging, provides a sensitive in vivo method to localize and monitor the progression of neuronal cell death and gliosis. Seizures were induced in rats by unilateral hippocampal injection of kainate. Magnetic resonance measurements were made from 1 to 84 days using proton spectroscopic imaging (¹H-MRSI), T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI). The results were compared with findings on histological sections. Decreased NAA and creatine levels and increased apparent diffusion coefficient of water were found in the ipsilateral hippocampus after 14 days where neuronal loss and gliosis were observed. In the contralateral hippocampus a significant increase of choline level was observed. These results suggest that ¹H-MRSI is a useful in vivo method for localizing neuronal loss and may also indicate additional pathological and metabolic alterations. In addition, DWI may be a useful method for in vivo detection of tissue alterations due to TLE.     

Localization of enkephalin-like immunoreactivity to identified axonal and neuronal populations of the rat hippocampus

The distribution of enkephalin-like immunoreactivity in the hippocampal formation of the rat was analyzed. Two specific projection systems are described. The first emerges from the hilus of the dentate gyrus and appears to terminate with notably large boutons on the proximal apical and, to a lesser extent, basal dendrites of hippocampal regio inferior pyramidal cells. This projection corresponds in source, position, and character to the hippocampal mossy fiber system. The second axonal population enters the temporal hippocampal formation from the medial wall of the subicular complex and follows the hippocampal fissure to occupy stratum lacunosum-moleculare of the hippocampus proper and the distal third of the dentate gyrus molecular layer; this pattern corresponds to the distribution of afferent input from the lateral entorhinal cortex and/or perirhinal area. Lesions of the hilus or retrohippocampal area caused a selective depletion of immunoreactivity in the mossy fiber fields and molecular layers of the dentate gyrus, respectively. Enkephalin-like immunoreactivity was found within the somata of three types of hippocampal neurons: (1) granule cells of the dentate gyrus, (2) occasional pyramidal shaped cells of field CA1 stratum pyramidale, and (3) varied scattered interneurons. Of this last group, two types of interneurons were consistently seen. The first occupy the border between stratum radiatum and stratum lacunosum-moleculare and extend processes at right angles to the long axis of the pyramidal cell dendrites, whereas the second lie within stratum radiatum of field CA1 and extend processes in alignment with the long axis of the pyramidal cell dendrites. Cells containing enkephalin-like immunoreacactivity were also observed in the subiculum and retrohippocampal region, most notably including layers II and III of the lateral entorhinal cortex-perirhinal area—the probable source of extrinsic immunoreactive input to the hippocampal formation. Intraventricular colchicine treatment intensified the immunoreactive staining of some hippocampal neurons but did not reveal any cell types not seen to be labeled in untreated rats.     

Differential regulation of HCN channel isoform expression in thalamic neurons of epileptic and non-epileptic rat strains

Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels represent the molecular substrate of the hyperpolarization-activated inward current (I_h). Although these channels act as pacemakers for the generation of rhythmic activity in the thalamocortical network during sleep and epilepsy, their developmental profile in the thalamus is not yet fully understood. Here we combined electrophysiological, immunohistochemical, and mathematical modeling techniques to examine HCN gene expression and I_h properties in thalamocortical relay (TC) neurons of the dorsal part of the lateral geniculate nucleus (dLGN) in an epileptic (WAG/Rij) compared to a non-epileptic (ACI) rat strain. Recordings of TC neurons between postnatal day (P) 7 and P90 in both rat strains revealed that I_h was characterized by higher current density, more hyperpolarized voltage dependence, faster activation kinetics, and reduced cAMP-sensitivity in epileptic animals. All four HCN channel isoforms (HCN1-4) were detected in dLGN, and quantitative analyses revealed a developmental increase of protein expression of HCN1, HCN2, and HCN4 but a decrease of HCN3. HCN1 was expressed at higher levels in WAG/Rij rats, a finding that was correlated with increased expression of the interacting proteins filamin A (FilA) and tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b). Analysis of a simplified computer model of the thalamic network revealed that the alterations of I_h found in WAG/Rij rats compensate each other in a way that leaves I_h availability constant, an effect that ensures unaltered cellular burst activity and thalamic oscillations. These data indicate that during postnatal developmental the hyperpolarizing shift in voltage dependency (resulting in less current availability) is compensated by an increase in current density in WAG/Rij thereby possibly limiting the impact of I_h on epileptogenesis. Because HCN3 is expressed higher in young versus older animals, HCN3 likely does not contribute to alterations in I_h in older animals.     

The cholinergic inhibition of afterhyperpolarization in rat hippocampus is independent of cAMP-dependent protein kinase

The possible involvement of protein kinase A (PKA) in the muscarinic inhibition of the slow afterhyperpolarizing current (I_AHP) was investigated in rat hippocampal pyramidal cells. I_AHP was recorded using the whole cell method in hippocampal slices, and Rp-cAMPs, a PKA antagonist, was applied intracellularly. The inhibition of I_AHP by carbachol was not affected by Rp-cAMPS. In contrast, Rp-cAMPS reduced the cAMP-dependent inhibition of I_AHP by norepinephrine. The results show that phosphorylation by PKA does not contribute to the muscarinic effect on I_AHP.     

Hyperpolarization-activated <Emphasis Type="Italic">I</Emphasis><Subscript>h</Subscript> pacemaker channel in the mammalian brain

In this review we describe the molecular structure of the hyperpolarization-activated cAMP-dependent I _h , or HCN, pacemaker channel. We discuss the channel functions and its subunit composition. Also, we hypothesize that spike-wave discharges in absence epilepsy are caused by these I _h channels located on the neurons of the thalamic reticular nucleus and layers three, four, and five of the somatosensory cortex. We describe the role of I _h channels on reticular and cortical neurons in normal behavior.     

Different structural correlates for verbal memory impairment in temporal lobe epilepsy with and without mesial temporal lobe sclerosis

Objectives: Memory impairment is one of the most prominent cognitive deficits in temporal lobe epilepsy (TLE). The overall goal of this study was to explore the contribution of cortical and hippocampal (subfield) damage to impairment of auditory immediate recall (AIMrecall), auditory delayed recall (ADMrecall), and auditory delayed recognition (ADMrecog) of the Wechsler Memory Scale III (WMS‐III) in TLE with (TLE–MTS) and without hippocampal sclerosis (TLE‐no). It was hypothesized that volume loss in different subfields determines memory impairment in TLE–MTS and temporal neocortical thinning in TLE‐no. Methods: T1 whole brain and T2‐weighted hippocampal magnetic resonance imaging and WMS‐III were acquired in 22 controls, 18 TLE–MTS, and 25 TLE‐no. Hippocampal subfields were determined on the T2 image. Free surfer was used to obtain cortical thickness averages of temporal, frontal, and parietal cortical regions of interest (ROI). MANOVA and stepwise regression analysis were used to identify hippocampal subfields and cortical ROI significantly contributing to AIMrecall, ADMrecall, and ADMrecog. Results: In TLE–MTS, AIMrecall was associated with cornu ammonis 3 (CA3) and dentate (CA3&DG) and pars opercularis, ADMrecall with CA1 and pars triangularis, and ADMrecog with CA1. In TLE‐no, AIMrecall was associated with CA3&DG and fusiform gyrus (FUSI), and ADMrecall and ADMrecog were associated with FUSI. Conclusion: The study provided the evidence for different structural correlates of the verbal memory impairment in TLE–MTS and TLE‐no. In TLE–MTS, the memory impairment was mainly associated by subfield‐specific hippocampal and inferior frontal cortical damage. In TLE‐no, the impairment was associated by mesial–temporal cortical and to a lesser degree hippocampal damage. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.     

Mislocalization of h channel subunits underlies h channelopathy in temporal lobe epilepsy

Many animal models of temporal lobe epilepsy (TLE) begin with status epilepticus (SE) followed by a latency period. Increased hippocampal pyramidal neuron excitability may contribute to seizures in TLE. I(h), mediated by h channels, regulates intrinsic membrane excitability by modulating synaptic integration and dampening dendritic calcium signaling. In a rat model of TLE, we found bidirectional changes in h channel function in CA1 pyramidal neurons. 1-2 d after SE, before onset of spontaneous seizures, physiological parameters dependent upon h channels were augmented and h channel subunit surface expression was increased. 28-30 d following SE, after onset of spontaneous seizures, h channel function in dendrites was reduced, coupled with diminished h channel subunit surface expression and relocalization of subunits from distal dendrites to soma. These results implicate h channel localization as a molecular mechanism influencing CA1 excitability in TLE.