Excitability Of CA1 Pyramidal Cells Research Articles

Environmental enrichment modulates intrinsic cellular excitability of hippocampal CA1 pyramidal cells in a housing duration and anatomical location-dependent manner

Housing animals in enriched environments (EEs) results in improved learning and memory (L&M) performance. While increased intrinsic cellular excitability in the hippocampal neurons might underlie the environmental enrichment-dependent L&M enhancement, literature in respect to this remains scarce and controversial. In this study, we explore whether intrinsic cellular excitability in hippocampal CA1 pyramidal cells is modulated differently, depending on housing duration and anatomical location of cells. Using in vitro patch clamp recordings in mice, we first demonstrate that cellular excitability of hippocampal CA1 pyramidal cells is significantly increased only in animals housed in an EE for a relatively short (<40 days) duration. Second, anatomical analysis shows that increased excitability is mainly restricted to the dorsal and proximal sections of the CA1 region. Further analysis reveals that the input resistance and the spike threshold, which are differently modulated by anatomical location and housing duration, respectively, may underlie the increased excitability. These results indicate that housing duration and anatomical location are crucial factors for environmental enrichment-dependent modulations of intrinsic excitability. While the dorsally restricted increase in excitability is in agreement with the specific up-regulation of L&M supported by the dorsal hippocampus, the selective modulation of the proximal area is in line with enhanced spatial abilities often observed after environmental enrichment. The housing duration specificity we observed here, together with previous findings, suggests that the modulation of some physiological properties by an environmental enrichment is transient. Finally, these results could coherently account for earlier controversial reports.

Short-term plasticity regulates the excitation/inhibition ratio and the temporal window for spike integration in CA1 pyramidal cells.

Many neurodevelopmental and neuropsychiatric disorders involve an imbalance between excitation and inhibition caused by synaptic alterations. The proper excitation/inhibition (E/I) balance is especially critical in CA1 pyramidal cells, because they control hippocampal output. Activation of Schaffer collateral axons causes direct excitation of CA1 pyramidal cells, quickly followed by disynaptic feedforward inhibition, stemming from synaptically induced firing of GABAergic interneurons. Both excitatory and inhibitory synapses are modulated by short-term plasticity, potentially causing dynamic tuning of the E/I ratio. However, the effects of short-term plasticity on the E/I ratio in CA1 pyramidal cells are not yet known. To determine this, we recorded disynaptic inhibitory postsynaptic currents and the E/I ratio in CA1 pyramidal cells in acute hippocampal slices from juvenile mice. We found that, whereas inhibitory synapses had paired-pulse depression, disynaptic inhibition instead had paired-pulse facilitation (≤200-ms intervals), caused by increased recruitment of feedforward interneurons. Although enhanced disynaptic inhibition helped to constrain paired-pulse facilitation of excitation, the E/I ratio was still larger on the second pulse, increasing pyramidal cell spiking. Surprisingly, this occurred without compromising the precision of spike timing. The E/I balance regulates the temporal spike integration window from multiple inputs; here, we showed that paired-pulse stimulation can broaden the spike integration window. Together, our findings show that the combined effects of short-term plasticity of disynaptic inhibition and monosynaptic excitation alter the E/I balance in CA1 pyramidal cells, leading to dynamic modulation of spike probability and the spike integration window. Short-term plasticity is therefore an important mechanism for modulating signal processing of hippocampal output.

Genetic background modulates impaired excitability of inhibitory neurons in a mouse model of Dravet syndrome

Dominant loss-of-function mutations in voltage-gated sodium channel NaV1.1 cause Dravet Syndrome, an intractable childhood-onset epilepsy. NaV1.1+/− Dravet Syndrome mice in C57BL/6 genetic background exhibit severe seizures, cognitive and social impairments, and premature death. Here we show that Dravet Syndrome mice in pure 129/SvJ genetic background have many fewer seizures and much less premature death than in pure C57BL/6 background. These mice also have a higher threshold for thermally induced seizures, fewer myoclonic seizures, and no cognitive impairment, similar to patients with Genetic Epilepsy with Febrile Seizures Plus. Consistent with this mild phenotype, mutation of NaV1.1 channels has much less physiological effect on neuronal excitability in 129/SvJ mice. In hippocampal slices, the excitability of CA1 Stratum Oriens interneurons is selectively impaired, while the excitability of CA1 pyramidal cells is unaffected. NaV1.1 haploinsufficiency results in increased rheobase and threshold for action potential firing and impaired ability to sustain high-frequency firing. Moreover, deletion of NaV1.1 markedly reduces the amplification and integration of synaptic events, further contributing to reduced excitability of interneurons. Excitability is less impaired in inhibitory neurons of Dravet Syndrome mice in 129/SvJ genetic background. Because specific deletion of NaV1.1 in forebrain GABAergic interneuons is sufficient to cause the symptoms of Dravet Syndrome in mice, our results support the conclusion that the milder phenotype in 129/SvJ mice is caused by lesser impairment of sodium channel function and electrical excitability in their forebrain interneurons. This mild impairment of excitability of interneurons leads to a milder disease phenotype in 129/SvJ mice, similar to Genetic Epilepsy with Febrile Seizures Plus in humans.

The dynamic impact of repeated stress on the hippocampal spatial map.

Stress alters the function of many physiological processes throughout the body, including in the brain. A neural circuit particularly vulnerable to the effects of stress is the hippocampus, a key component of the episodic and spatial memory system in both humans and rodents. Earlier studies have provided snapshots of morphological, molecular, physiological and behavioral changes in the hippocampus following either acute or repeated stress. However, the cumulative impact of repeated stress on in vivo hippocampal physiology remains unexplored. Here we report the stress-induced modulation of the spatially receptive fields of the hippocampal CA1 'place cells' as mice explore familiar and novel tracks after 5 and 10 days of immobilization stress. We find that similar to what has been observed following acute stress, five days of repeated stress results in decreased excitability of CA1 pyramidal cells. Following ten days of chronic stress, however, this decreased hippocampal excitability is no longer evident, suggesting adaptation may have occurred. In addition to these changes in neuronal excitability, we find deficient context discrimination, wherein both short-term and chronic stress impair the ability of the hippocampus to unambiguously distinguish novel and familiar environments. These results suggest that a loss of network flexibility may underlie some of the behavioral deficits accompanying chronic stress.

Role of small conductance Ca²⁺-activated K⁺ channels in controlling CA1 pyramidal cell excitability.

Small-conductance Ca(2+)-activated K(+) (SK or K(Ca)2) channels are widely expressed in the CNS. In several types of neurons, these channels were shown to become activated during repetitive firing, causing early spike frequency adaptation. In CA1 pyramidal cells, SK channels in dendritic spines were shown to regulate synaptic transmission. However, the presence of functional SK channels in the somata and their role in controlling the intrinsic firing of these neurons has been controversial. Using whole-cell voltage-clamp and current-clamp recordings in acute hippocampal slices and focal applications of irreversible and reversible SK channel blockers, we provide evidence that functional SK channels are expressed in the somata and proximal dendrites of adult rat CA1 pyramidal cells. Although these channels can generate a medium duration afterhyperpolarizing current, they play only an auxiliary role in controlling the intrinsic excitability of these neurons, secondary to the low voltage-activating, noninactivating K(V)7/M channels. As long as K(V)7/M channels are operative, activation of SK channels during repetitive firing does not notably affect the spike output of CA1 pyramidal cells. However, when K(V)7/M channel activity is compromised, SK channel activation significantly and uniquely reduces spike output of these neurons. Therefore, proximal SK channels provide a "second line of defense" against intrinsic hyperexcitability, which may play a role in multiple conditions in which K(V)7/M channels activity is compromised, such as hyposmolarity.

A novel short-term plasticity of intrinsic excitability in the hippocampal CA1 pyramidal cells.

Changes in neuronal activity often trigger compensatory mechanisms aimed at regulating network activity homeostatically. Here we have identified and characterized a novel form of compensatory short-term plasticity of membrane excitability, which develops early after the eye-opening period in rats (P16-19 days) but not before that developmental stage (P9-12 days old). Holding the membrane potential of CA1 neurons right below the firing threshold from 15 s to several minutes induced a potentiation of the repolarizing phase of the action potentials that contributed to a decrease in the firing rate of CA1 pyramidal neurons in vitro. Furthermore, the mechanism for inducing this plasticity required the action of intracellular Ca(2+) entering through T-type Ca(2+) channels. This increase in Ca(2+) subsequently activated the Ca(2+) sensor K(+) channel interacting protein 3, which led to the increase of an A-type K(+) current. These results suggest that Ca(2+) modulation of somatic A-current represents a new form of homeostatic regulation that provides CA1 pyramidal neurons with the ability to preserve their firing abilities in response to membrane potential variations on a scale from tens of seconds to several minutes.

Characterization of altered intrinsic excitability in hippocampal CA1 pyramidal cells of the Aβ-overproducing PDAPP mouse

Transgenic mice that accumulate Aβ peptides in the CNS are commonly used to interrogate functional consequences of Alzheimer's disease-associated amyloidopathy. In addition to changes to synaptic function, there is also growing evidence that changes to intrinsic excitability of neurones can arise in these models of amyloidopathy. Furthermore, some of these alterations to intrinsic properties may occur relatively early within the age-related progression of experimental amyloidopathy. Here we report a detailed comparison between the intrinsic excitability properties of hippocampal CA1 pyramidal neurones in wild-type (WT) and PDAPP mice. The latter is a well-established model of Aβ accumulation which expresses human APP harbouring the Indiana (V717F) mutation. At the age employed in this study (9–10 months) CNS Abeta was elevated in PDAPP mice but significant plaque pathology was absent. PDAPP mice exhibited no differences in subthreshold intrinsic properties including resting potential, input resistance, membrane time constant and sag. When CA1 cells of PDAPP mice were given depolarizing stimuli of various amplitudes they initially fired at a higher frequency than WT cells. Commensurate with this, PDAPP cells exhibited a larger fast afterdepolarizing potential. PDAPP mice had narrower spikes but action potential threshold, rate of rise and peak were not different. Thus not all changes seen in our previous studies of amyloidopathy models were present in PDAPP mice; however, narrower spikes, larger ADPs and the propensity to fire at higher frequencies were consistent with our prior work and thus may represent robust, cross-model, indices of amyloidopathy.This article is part of a Special Issue entitled ‘Neurodevelopment Disorder’.

Histamine enhances excitability and may augment neuroprotection in the Syrian hamster hippocampus

Previous studies showed that the neuromodulator histamine (HA) increases hibernation bout duration and, in non‐hibernating species, attenuates ischemic neuronal damage. We tested the hypotheses that: (1) HA directly enhances CA1 and CA3 Syrian hamster (Mesocricetus auratus) pyramidal cell excitability and (2) HA promotes recovery from an anoxic insult. HA (10μM) was applied directly to hippocampal slices and evoked responses (ERs) were recorded before, during, and after HA perfusion at 30ºC. ERs were also recorded before, during, and after a 15 min anoxic insult (95%N2/5%CO2). We found that HA increased ERs recorded from the CA1 region (23% increase, P&lt; 0.05) and shortened the latency to the ER peaks (16–26% decrease, P&lt;0.01) in 7 slices from 5 hamsters. In the CA3 region, HA had similar, though smaller, effects on latency and amplitude. Following anoxia, in the presence of HA, 5 slices recovered faster, 2 slower, and 1 was unaffected vs. slices without HA. Data are consistent with both hypotheses and suggest that HA has multiple, synergistic effects on pyramidal cells. Moreover, the observed HA‐induced enhanced excitability of pyramidal cells supports the view that these cells play a key role in the neural pathway regulating hibernation bout duration. The increased rate of recovery suggests that HA also has a neuroprotective role, ensuring reliable signal processing in a hibernating hamster.

Acute Alterations of Somatodendritic Action Potential Dynamics in Hippocampal CA1 Pyramidal Cells after Kainate-Induced Status Epilepticus in Mice

Pathophysiological remodeling processes at an early stage of an acquired epilepsy are critical but not well understood. Therefore, we examined acute changes in action potential (AP) dynamics immediately following status epilepticus (SE) in mice. SE was induced by intraperitoneal (i.p.) injection of kainate, and behavioral manifestation of SE was monitored for 3–4 h. After this time interval CA1 pyramidal cells were studied ex vivo with whole-cell current-clamp and Ca2+ imaging techniques in a hippocampal slice preparation. Following acute SE both resting potential and firing threshold were modestly depolarized (2–5 mV). No changes were seen in input resistance or membrane time constant, but AP latency was prolonged and AP upstroke velocity reduced following acute SE. All cells showed an increase in AP halfwidth and regular (rather than burst) firing, and in a fraction of cells the notch, typically preceding spike afterdepolarization (ADP), was absent following acute SE. Notably, the typical attenuation of backpropagating action potential (b-AP)-induced Ca2+ signals along the apical dendrite was strengthened following acute SE. The effects of acute SE on the retrograde spread of excitation were mimicked by applying the Kv4 current potentiating drug NS5806. Our data unveil a reduced somatodendritic excitability in hippocampal CA1 pyramidal cells immediately after acute SE with a possible involvement of both Na+ and K+ current components.

Histamine receptor expression, hippocampal plasticity and ammonia in histidine decarboxylase knockout mice.

Genetic ablation of the histamine producing enzyme histidine decarboxylase (HDC) leads to alteration in exploratory behaviour and hippocampus-dependent learning. We investigated how brain histamine deficiency in HDC knockout mice (HDC KO) affects hippocampal excitability, synaptic plasticity, and the expression of histamine receptors. No significant alterations in: basal synaptic transmission, long-term potentiation (LTP) in the Schaffer collateral synapses, histamine-induced transient changes in the CA1 pyramidal cell excitability, and the expression of H1 and H2 receptor mRNAs were found in hippocampal slices from HDC KO mice. However, when compared to WT mice, HDC KO mice demonstrated: 1. a stronger enhancement of LTP by histamine, 2. a stronger impairment of LTP by ammonia, 3. no long-lasting potentiation of population spikes by histamine, 4. a decreased expression of H3 receptor mRNA, and 5. less potentiation of population spikes by H3 receptor agonism. Parallel measurements in the hypothalamic tuberomamillary nucleus, the origin of neuronal histamine, demonstrated an increased expression of H3 receptors in HDC KO mice without any changes in the spontaneous firing of "histaminergic" neurons without histamine and their responses to the H3 receptor agonist (R)-α-methylhistamine. We conclude that the absence of neuronal histamine results in subtle changes in hippocampal synaptic transmission and plasticity associated with alteration in the expression of H3 receptors.

Short- and Long-Lasting Consequences ofIn VivoNicotine Treatment on Hippocampal Excitability

The potential for relapse following cessation of drug use can last for years, implying the induction of stable changes in neural circuitry. In hippocampal slices from rats treated with nicotine for 1 week, withdrawal from nicotine in vivo produces an increase in CA1 pyramidal cell excitability that persists up to 9 months. Immediately upon drug cessation, the enhanced excitability depends on input from regions upstream of CA1, while the long-term excitability change (> 4 weeks) is expressed as an increase in the intrinsic excitability of CA1 neurons. Re-exposure to nicotine in vitro restores hippocampal function to control levels via activation of high-affinity nicotinic acetylcholine receptors after 1 d of withdrawal, but not at times >4 weeks. Thus, nicotine in vivo first induces homeostatic adaptations followed by other more robust neural changes. These mechanisms may contribute to hippocampal localized cue-motivated reinstatement of drug-seeking and/or cognitive deficits observed during withdrawal.

Anti-Glucocorticoid Gene Therapy Reverses the Impairing Effects of Elevated Corticosterone on Spatial Memory, Hippocampal Neuronal Excitability, and Synaptic Plasticity

Moderate release of the major stress hormones, glucocorticoids (GCs), improves hippocampal function and memory. In contrast, excessive or prolonged elevations produce impairments. Enzymatic degradation and reformation of GCs help to maintain optimal levels within target tissues, including the brain. We hypothesized that expressing a GC-degrading enzyme in hippocampal neurons would attenuate the negative impact of an excessive elevation in GC levels on synaptic physiology and spatial memory. We tested this by expressing 11-beta-hydroxysteroid dehydrogenase (type II) in dentate gyrus granule cells during a 3 d GC treatment followed by examination of synaptic responses in hippocampal slices or spatial performance in the Morris water maze. In adrenalectomized rats with basal GC replacement, additional GC treatments for 3 d reduced synaptic strength and promoted the expression of long-term depression at medial perforant path synapses, increased granule cell and CA1 pyramidal cell excitability, and impaired spatial reference memory (without influencing learning). Expression of 11-beta-hydroxysteroid dehydrogenase (type II), mostly in mature dentate gyrus granule cells, reversed the effects of high GC levels on granule cell and pyramidal cell excitability, perforant path synaptic plasticity, and spatial memory. These data demonstrate the ability of neuroprotective gene expression limited to a specific cell population to both locally and trans-synaptically offset neurophysiological disruptions produced by prolonged increases in circulating stress hormones. This report supplies the first physiological explanation for previously demonstrated cognitive sparing by anti-stress gene therapy approaches and lends additional insight into the hippocampal processes that are important for memory.

Cholinergic Modulation Differs between Basal and Apical Dendritic Excitation of Hippocampal CA1 Pyramidal Cells

We hypothesize that endogenous cholinergic modulation of dendritic processing of hippocampal CA1 is layer specific, and it specifically enhances spike output resulting from basal as compared with the apical dendritic excitation. Laminar profiles of evoked field potentials were recorded in the CA1 area of urethane-anesthetized rats using multichannel silicon probes and analyzed as current source density. High-frequency stimulation of the pontis oralis (PnO) attenuated the midapical more than the basal or distal apical dendritic excitatory sink. Population spike (PS) and excitatory sink-PS potentiation resulting from basal dendritic excitation were facilitated, while the PS evoked by apical dendritic stimulation was attenuated by PnO stimulation. Perfusion of cholinergic agonist carbachol onto hippocampal slices in vitro also attenuated the apical more than the basal dendritic excitatory postsynaptic potentials. Excitatory sink attenuation and PS changes after PnO stimulation were blocked by systemic or local scopolamine and by intracerebroventricular (icv) M1 receptor antagonist pirenzepine but not by icv M2 receptor antagonist AFDX-116 or nicotinic antagonists. However, a hippocampal theta rhythm activated by PnO stimulation was blocked by systemic but not by local scopolamine. We conclude that endogenous acetylcholine mediates a stronger presynaptic inhibition of the midapical than basal and distal apical excitation mainly through M1 receptors.

Sleep fragmentation reduces hippocampal CA1 pyramidal cell excitability and response to adenosine

Sleep fragmentation (SF) impairs the restorative/cognitive benefits of sleep via as yet unidentified alterations in neural physiology. Previously, we found that hippocampal synaptic plasticity and spatial learning are impaired in a rat model of SF which utilizes a treadmill to awaken the animals every 2min, mimicking the frequency of awakenings observed in human sleep apnea patients. Here, we investigated the cellular mechanisms responsible for these effects, using whole-cell patch-clamp recordings. 24h of SF decreased the excitability of hippocampal CA1 pyramidal neurons via decreased input resistance, without alterations in other intrinsic membrane or action potential properties (when compared to cage controls, or to exercise controls that experienced the same total amount of treadmill movement as SF rats). Contrary to our initial prediction, the hyperpolarizing response to bath applied adenosine (30μM) was reduced in the CA1 neurons of SF treated rats. Our initial prediction was based on the evidence that sleep loss upregulates cortical adenosine A1 receptors; however, the present findings are consistent with a very recent report that hippocampal A1 receptors are not elevated by sleep loss. Thus, increased adenosinergic inhibition is unlikely to be responsible for reduced hippocampal long-term potentiation in SF rats. Instead, the reduced excitability of CA1 pyramidal neurons observed here may contribute to the loss of hippocampal long-term potentiation and hippocampus-dependent cognitive impairments associated with sleep disruption.

Short Trains of Theta Frequency Stimulation Enhance CA1 Pyramidal Neuron Excitability in the Absence of Synaptic Potentiation

Although plasticity at excitatory synapses is widely studied as a mechanism for memory formation, less is known about the properties and mechanisms underlying activity-dependent changes in excitability. Using extracellular and intracellular recordings in hippocampal slices, we find that short trains (2-3 s) of Schaffer collateral fiber stimulation delivered at 5 Hz induce a robust and persistent increase in the excitability of CA1 pyramidal cells in the absence of synaptic potentiation. This change in excitability is input specific, NMDA receptor dependent, and is not accompanied by lasting changes in either inhibitory synaptic transmission or somatic excitability. Although many of these properties are similar to those seen in synaptic long-term potentiation (LTP), the increase in CA1 pyramidal cell excitability was not blocked by inhibitors of several protein kinases required for the induction of LTP by theta frequency stimulation. Instead, 5 Hz stimulation-induced changes in neuronal excitability were blocked by inhibitors of the protein phosphatase calcineurin. Together, our results suggest that very brief bouts of theta frequency synaptic activity induce a selective, persistent, and dendritically localized increase in CA1 pyramidal cell excitability that might have an important role in both information storage and metaplasticity.

Ca v1.2 calcium channels modulate the spiking pattern of hippocampal pyramidal cells

Ca v1.2 L-type calcium channels support hippocampal synaptic plasticity, likely by facilitating dendritic Ca 2+ influx evoked by action potentials (AP) back-propagated from the soma. Ca 2+ influx into hippocampal neurons during somatic APs is sufficient to activate signalling pathways associated with late phase LTP. Thus, mechanisms controlling AP firing of hippocampal neurons are of major functional relevance. We examined the excitability of CA1 pyramidal cells using somatic current-clamp recordings in brain slices from control type mice and mice with the Ca v1.2 gene inactivated in principal hippocampal neurons. Lack of the Ca v1.2 protein did not affect either affect basic characteristics, such as resting membrane potential and input resistance, or parameters of single action potentials (AP) induced by 5 ms depolarising current pulses. However, CA1 hippocampal neurons from control and mutant mice differed in their patterns of AP firing during 500 ms depolarising current pulses: threshold voltage for repetitive firing was shifted significantly by about 5 mV to more depolarised potentials in the mutant mice ( p < 0.01), and the latency until firing of the first AP was prolonged (73.2 ± 6.6 ms versus 48.1 ± 7.8 ms in control; p < 0.05). CA1 pyramidal cells from the mutant mice also showed a lowered initial spiking frequency within an AP train. In control cells, isradipine had matching effects, while BayK 8644 facilitated spiking. Our data demonstrate that Ca v1.2 channels are involved in regulating the intrinsic excitability of CA1 pyramidal neurons. This cellular mechanism may contribute to the known function of Ca v1.2 channels in supporting synaptic plasticity and memory.

Activity-Dependent Depression of Local Excitatory Connections in the CA1 Region of Mouse Hippocampus

The existence of recurrent excitatory synapses between pyramidal cells in the hippocampal CA1 region has been known for some time yet little is known about activity-dependent forms of plasticity at these synapses. Here we demonstrate that under certain experimental conditions, Schaffer collateral/commissural fiber stimulation can elicit robust polysynaptic excitatory postsynaptic potentials due to recurrent synaptic inputs onto CA1 pyramidal cells. In contrast to CA3 pyramidal cell inputs, recurrent synapses onto CA1 pyramidal cells exhibited robust paired-pulse depression and a sustained, but rapidly reversible, depression in response to low-frequency trains of Schaffer collateral fiber stimulation. Blocking GABA(B) receptors abolished paired-pulse depression but had little effect on low-frequency stimulation (LFS)-induced depression. Instead, LFS-induced depression was significantly attenuated by an inhibitor of A1 type adenosine receptors. Blocking the postsynaptic effects of GABA(B) and A1 receptor activation on CA1 pyramidal cell excitability with an inhibitor of G-protein-activated inwardly rectifying potassium channels had no effect on either paired-pulse depression or LFS-induced depression. Thus activation of presynaptic GABA(B) and adenosine receptors appears to have an important role in activity-dependent depression at recurrent synapses. Together, our results indicate that CA3-CA1 and CA1-CA1 synapses exhibit strikingly different forms of short-term synaptic plasticity and suggest that activity-dependent changes in recurrent synaptic transmission can transform the CA1 region from a sparsely connected recurrent network into a predominantly feedforward circuit.

M-Channels (Kv7/KCNQ Channels) That Regulate Synaptic Integration, Excitability, and Spike Pattern of CA1 Pyramidal Cells Are Located in the Perisomatic Region

To understand how electrical signal processing in cortical pyramidal neurons is executed by ion channels, it is essential to know their subcellular distribution. M-channels (encoded by Kv7.2-Kv7.5/KCNQ2-KCNQ5 genes) have multiple important functions in neurons, including control of excitability, spike afterpotentials, adaptation, and theta resonance. Nevertheless, the subcellular distribution of these channels has remained elusive. To determine the M-channel distribution within CA1 pyramidal neurons, we combined whole-cell patch-clamp recording from the soma and apical dendrite with focal drug application, in rat hippocampal slices. Both a M-channel opener (retigabine [N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester]) and a blocker (XE991 [10,10-bis(4-pyridinylmethyl)-9(10H)-antracenone]) changed the somatic subthreshold voltage response but had no observable effect on local dendritic responses. Under conditions promoting dendritic Ca2+ spikes, local somatic but not dendritic application of M-channel blockers (linopirdine and XE991) enhanced the Ca2+ spikes. Simultaneous dendritic and somatic whole-cell recordings showed that the medium afterhyperpolarization after a burst of spikes underwent strong attenuation along the apical dendrite and was fully blocked by somatic XE991 application. Finally, by combining patch-clamp and extracellular recordings with computer simulations, we found that perisomatic M-channels reduce the summation of EPSPs. We conclude that functional M-channels appear to be concentrated in the perisomatic region of CA1 pyramidal neurons, with no detectable M-channel activity in the distal apical dendrites.

Persistent changes in action potential broadening and the slow afterhyperpolarization in rat CA1 pyramidal cells after febrile seizures

Febrile (fever-induced) seizures (FS) are the most common form of seizures during childhood and have been associated with an increased risk of epilepsy later in life. The relationship of FS to subsequent epilepsy is, however, still controversial. Insights from animal models do indicate that especially complex FS are harmful to the developing brain and contribute to a hyperexcitable state that may persist for life. Here, we determined long-lasting changes in neuronal excitability of rat hippocampal CA1 pyramidal cells after prolonged (complex) FS induced by hyperthermia on postnatal day 10. We show that hyperthermia-induced seizures at postnatal day 10 induce a long-lasting increase in the hyperpolarization-activated current I(h). Furthermore, we show that a reduction in the amount of spike broadening and in the amplitude of the slow afterhyperpolarization following FS are also likely to contribute to the hyperexcitability of the hippocampus long term.

Axo-Somatic and Apical Dendritic Kv7/M Channels Differentially Regulate the Intrinsic Excitability of Adult Rat CA1 Pyramidal Cells

Kv7/KCNQ/M channel subunits are widely expressed in peripheral and central neurons, where they give rise to a muscarinic-sensitive, subthreshold, and noninactivating K+ current (M current). Immunohistochemical data suggest that Kv7/M channels are expressed in both axons, somata and dendrites, but their distinctive roles in these compartments are not known. Here we used intracellular microelectrode recordings to monitor the effects of selective Kv7/M channel modulators focally applied to the axo-somatic region and to the apical dendrites of adult rat CA1 pyramidal cells. We show that both compartments express functional Kv7/M channels that synergistically control intrinsic neuronal excitability, albeit in different ways. Axo-somatic Kv7/M channels activate during the spike afterdepolarization (ADP) and counteract the depolarizing drive furnished by conjointly activated persistent Na+ channels. Thereby they limit the size and duration of the spike ADP and prevent its escalation into a somatic spike burst. Apical dendritic Kv7/M channels do not ordinarily regulate the somatic spike ADP and spike output. In hyperexcitable conditions that promote Ca2+ electrogenesis in these dendrites, they elevate the threshold for initiating Ca2+ spikes and associated downstream spike bursts. Thus the concerted activity of Kv7/M channels in both compartments serves to reduce the propensity to generate self-sustained burst responses and fosters a regular, stimulus-graded spike output of the neuron. Given that the activity of Kv7/M channels is regulated by multiple neurotransmitters, they may provide a substrate for neuromodulation of neuronal input/output relations at both the axo-somatic and apical dendritic regions.