The firing patterns of spinal neurons: in situ patch‐clamp recordings reveal a key role for potassium currents

Neuron firing patterns underpin the detection and processing of stimuli, influence synaptic interactions, and contribute to the function of networks. To understand how intrinsic membrane properties determine firing patterns, we investigated the biophysical basis of single and repetitive firing in spinal neurons of hatchling Xenopus laevis tadpoles, a well‐understood vertebrate model; experiments were conducted in situ. Primary sensory Rohon–Beard (RB) neurons fire singly in response to depolarising current, and dorsolateral (DL) interneurons fire repetitively. RB neurons exhibited a large tetrodotoxin‐sensitive sodium current; in DL neurons, the sodium current density was significantly lower. High‐voltage‐activated calcium currents were similar in both neuron types. There was no evidence of persistent sodium currents, low‐voltage‐activated calcium currents, or hyperpolarisation‐activated currents. In RB neurons, the potassium current was dominated by a tetraethylammonium‐sensitive slow component (I_Ks); a fast component (I_Kf), sensitive to 4‐aminopyridine, predominated in DL neurons. Sequential current‐clamp and voltage‐clamp recordings in individual neurons suggest that high densities of I_Ks prevent repetitive firing; where I_Ks is small, I_Kf density determines the frequency of repetitive firing. Intermediate densities of I_Ks and I_Kf allow neurons to fire a few additional spikes on strong depolarisation; this property typifies a novel subset of RB neurons, and may activate escape responses. We discuss how this ensemble of currents and firing patterns underpins the operation of the Xenopus locomotor network, and suggest how simple mechanisms might underlie the similar firing patterns seen in the neurons of diverse species.     

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.     

Ionic contributions to the oscillatory firing activity of rat Purkinje cells in vitro

Oscillatory firing activity in cerebellar Purkinje cells (PCs) can be maintained by intrinsic ionic conductances in the apparent absence of excitatory and inhibitory synaptic input as demonstrated by application of TTX or antagonists of amino acid-mediated transmission or both. Bursting activity in these cells is associated with a region of ZSR (zero slope resistance, the beginning part of a negative slope resistance region) of the whole cell quasi-steady-state I–V relationship. Blockade of Na⁺ current by TTX unmasked the ZSR region in all PCs tested. Based on current and voltage clamp experiments, hyperpolarization-activated cation current (I_h) participates in the rhythmic firing activity by influencing the amplitude and duration of the interburst interval and the resultant pattern of the burst generation. Blockade of I_h with cesium (Cs⁺) retards the membrane rebound from the after-hyperpolarization and results in longer and more negative hyperpolarization between bursts. However, Cs⁺ did not affect the presence and characteristic of the ZSR region of the whole cell quasi-steady-state I–V curve.     

Frequency‐dependent regulation of intrinsic excitability by voltage‐activated membrane conductances,computational modeling and dynamic clamp

As one of the most unique properties of nerve cells, their intrinsic excitability allows them to transform synaptic inputs into action potentials. This process reflects a complex interplay between the synaptic inputs and the voltage‐dependent membrane currents of the postsynaptic neuron. While neurons in natural conditions mostly fire under the action of intense synaptic bombardment and receive fluctuating patterns of excitation and inhibition, conventional techniques to characterize intrinsic excitability mainly utilize static means of stimulation. Recently, we have shown that voltage‐gated membrane currents regulate the firing responses under current step stimulation and under physiologically more realistic inputs in a differential manner. At the same time, a multitude of neuron types have been shown to exhibit some form of subthreshold resonance that potentially allows them to respond to synaptic inputs in a frequency‐selective manner. In this study, we performed virtual experiments in computational models of neurons to examine how specific voltage‐gated currents regulate their excitability under simulated frequency‐modulated synaptic inputs. The model simulations and subsequent dynamic clamp experiments on mouse hippocampal pyramidal neurons revealed that the impact of voltage‐gated currents in regulating the firing output is strongly frequency‐dependent and mostly affecting the synaptic integration at theta frequencies. Notably, robust frequency‐dependent regulation of intrinsic excitability was observed even when conventional analysis of membrane impedance suggested no such tendency. Consequently, plastic or homeostatic regulation of intrinsic membrane properties can tune the frequency selectivity of neuron populations in a way that is not readily expected from subthreshold impedance measurements.     

Resonance properties of different neuronal populations in the immature mouse neocortex

In vivo recordings in the immature neocortex revealed spontaneous and sensory‐driven oscillatory activity from delta (0.5–4 Hz) to gamma (30–100 Hz) frequencies. In order to investigate whether the resonance properties of distinct neuronal populations in the immature neocortex contribute to these network oscillations, we performed whole‐cell patch‐clamp recordings from visually identified neurons in tangential and coronal neocortical slices from postnatal day (P)0–P7 C57Bl/6 mice. Subthreshold resonance was analysed by sinusoidal current injection of varying frequency. All Cajal–Retzius cells showed subthreshold resonance, with an average frequency of 2.6 ± 0.1 Hz (n = 60), which was massively reduced by ZD7288, a blocker of hyperpolarization‐activated cation currents. Approximately 65.6% (n = 61) of the supragranular pyramidal neurons showed subthreshold resonance, with an average frequency of 1.4 ± 0.1 Hz (n = 40). Application of Ni²⁺ suppressed subthreshold resonance, suggesting that low‐threshold calcium currents contribute to resonance in these neurons. Approximately 63.6% (n = 77) of the layer V pyramidal neurons showed subthreshold resonance, with an average frequency of 1.4 ± 0.2 Hz (n = 49), which was abolished by ZD7288. Only 44.1% (n = 59) of the subplate neurons showed subthreshold resonance, with an average frequency of 1.3 ± 0.2 Hz (n = 26) and a small resonance strength. In summary, these results demonstrate that neurons in all investigated layers show resonance behavior, with either hyperpolarization‐activated cation or low‐threshold calcium currents contributing to the subthreshold resonance. The observed resonance frequencies are in the range of slow activity patterns observed in the immature neocortex, suggesting that subthreshold resonance may support the generation of this activity.     

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.     

Generation of resonance‐dependent oscillation by mGluR‐I activation switches single spiking to bursting in mesencephalic trigeminal sensory neurons

The primary sensory neurons supplying muscle spindles of jaw‐closing muscles are unique in that they have their somata in the mesencephalic trigeminal nucleus (MTN) in the brainstem, thereby receiving various synaptic inputs. MTN neurons display bursting upon activation of glutamatergic synaptic inputs while they faithfully relay respective impulses arising from peripheral sensory organs. The persistent sodium current (I_NaP) is reported to be responsible for both the generation of bursts and the relay of impulses. We addressed how I_NaP is controlled either to trigger bursts or to relay respective impulses as single spikes in MTN neurons. Protein kinase C (PKC) activation enhanced I_NaP only at low voltages. Spike generation was facilitated by PKC activation at membrane potentials more depolarized than the resting potential. By injection of a ramp current pulse, a burst of spikes was triggered from a depolarized membrane potential whereas its instantaneous spike frequency remained almost constant despite the ramp increases in the current intensity beyond the threshold. A puff application of glutamate preceding the ramp pulse lowered the threshold for evoking bursts by ramp pulses while chelerythrine abolished such effects of glutamate. Dihydroxyphenylglycine, an agonist of mGluR1/5, also caused similar effects, and increased both the frequency and impedance of membrane resonance. Immunohistochemistry revealed that glutamatergic synapses are made onto the stem axons, and that mGluR1/5 and Nav1.6 are co‐localized in the stem axon. Taken together, glutamatergic synaptic inputs onto the stem axon may be able to switch the relaying to the bursting mode.     

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.     

Muscarinic modulation of TREK currents in mouse sympathetic superior cervical ganglion neurons

Muscarinic receptors play a key role in the control of neurotransmission in the autonomic ganglia, which has mainly been ascribed to the regulation of potassium M‐currents and voltage‐dependent calcium currents. Muscarinic agonists provoke depolarization of the membrane potential and a reduction in spike frequency adaptation in postganglionic neurons, effects that may be explained by M‐current inhibition. Here, we report the presence of a riluzole‐activated current (I_RIL) that flows through the TREK‐2 channels, and that is also inhibited by muscarinic agonists in neurons of the mouse superior cervical ganglion (mSCG). The muscarinic agonist oxotremorine‐M (Oxo‐M) inhibited the I_RIL by 50%, an effect that was abolished by pretreatment with atropine or pirenzepine, but was unaffected in the presence of himbacine. Moreover, these antagonists had similar effects on single‐channel TREK‐2 currents. I_RIL inhibition was unaffected by pretreatment with pertussis toxin. The protein kinase C blocker bisindolylmaleimide did not have an effect, and neither did the inositol triphosphate antagonist 2‐aminoethoxydiphenylborane. Nevertheless, the I_RIL was markedly attenuated by the phospholipase C (PLC) inhibitor ET‐18‐OCH3. Finally, the phosphatidylinositol‐3‐kinase/phosphatidylinositol‐4‐kinase inhibitor wortmannin strongly attenuated the I_RIL, whereas blocking phosphatidylinositol 4,5‐bisphosphate (PIP₂) depletion consistently prevented I_RIL inhibition by Oxo‐M. These results demonstrate that TREK‐2 currents in mSCG neurons are inhibited by muscarinic agonists that activate M1 muscarinic receptors, reducing PIP₂ levels via a PLC‐dependent pathway. The similarities between the signaling pathways regulating the I_RIL and the M‐current in the same neurons reflect an important role of this new pathway in the control of autonomic ganglia excitability.     

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.     

In vivo assessment of HCN channel current (Ih) in human motor axons

The “Trond” protocol of nerve excitability tests has been used widely to assess axonal function in peripheral nerve. In this study, the routine Trond protocol was expanded to refine assessment of cAMP‐dependent, hyperpolarization‐activated current (I_h) activity. I_h activity is generated by hyperpolarization‐activated, cyclic nucleotide–modulated (HCN) channels in response to hyperpolarization. It limits activity‐dependent hyperpolarization, contributes to neuronal automaticity, and is implicated in chronic pain states. Published data regarding I_h activity in motor nerve are scant. We used additional strong, prolonged hyperpolarizing conditioning stimuli in the threshold electrotonus component of the Trond protocol to demonstrate the time‐course of activation of I_h in motor axons. Fifteen healthy volunteers were tested on four occasions during 1 week. I_h action was revealed in the threshold electrotonus by the limiting and often reversal, after about 100 ms, of the threshold increase caused by strong hyperpolarizing currents. Statistical analysis by repeated‐measures analysis of variance enabled confidence limits to be established for variation between subjects and within subjects. The results demonstrate that, of all the excitability parameters, those dependent on I_h were the most characteristic of an individual, because variance between subjects was more than four times the variance within subjects. This study demonstrates a reliable method for in vivo assessment of I_h, and also serves to document the normal variability in nerve excitability properties within subjects. Muscle Nerve, 2010     

Identification and modelling of fast and slow Ih current components in vestibular ganglion neurons

Previous experimental data indicates the hyperpolarization‐activated cation (I_h) current, in the inner ear, consists of two components [different hyperpolarization‐activated cyclic nucleotide‐gated (HCN) subunits] which are impossible to pharmacologically isolate. To confirm the presence of these two components in vestibular ganglion neurons we have applied a parameter identification algorithm which is able to discriminate the parameters of the two components from experimental data. Using simulated data we have shown that this algorithm is able to identify the parameters of two populations of non‐inactivated ionic channels more accurately than a classical method. Moreover, the algorithm was demonstrated to be insensitive to the key parameter variations. We then applied this algorithm to I_h current recordings from mouse vestibular ganglion neurons. The algorithm revealed the presence of a high‐voltage‐activated slow component and a low‐voltage‐activated fast component. Finally, the electrophysiological significance of these two I_h components was tested individually in computational vestibular ganglion neuron models (sustained and transient), in the control case and in the presence of cAMP, an intracellular cyclic nucleotide that modulates HCN channel activity. The results suggest that, first, the fast and slow components modulate differently the action potential excitability and the excitatory postsynaptic potentials in both sustained and transient vestibular neurons and, second, the fast and slow components, in the control case, provide different information about characteristics of the stimulation and this information is significantly modified after modulation by cAMP.     

Sodium and calcium mechanisms of rhythmic bursting in excitatory neural networks of the pre‐Bötzinger complex: a computational modelling study

The neural mechanisms generating rhythmic bursting activity in the mammalian brainstem, particularly in the pre‐Bötzinger complex (pre‐BötC), which is involved in respiratory rhythm generation, and in the spinal cord (e.g. locomotor rhythmic activity) that persist after blockade of synaptic inhibition remain poorly understood. Experimental studies in rodent medullary slices containing the pre‐BötC identified two mechanisms that could potentially contribute to the generation of rhythmic bursting: one based on the persistent Na⁺ current (I_NaP), and the other involving the voltage‐gated Ca²⁺ current (I_Ca) and the Ca²⁺‐activated nonspecific cation current (I_CAN), activated by intracellular Ca²⁺ accumulated from extracellular and intracellular sources. However, the involvement and relative roles of these mechanisms in rhythmic bursting are still under debate. In this theoretical/modelling study, we investigated Na⁺‐dependent and Ca²⁺‐dependent bursting generated in single cells and heterogeneous populations of synaptically interconnected excitatory neurons with I_NaP and I_Ca randomly distributed within populations. We analysed the possible roles of network connections, ionotropic and metabotropic synaptic mechanisms, intracellular Ca²⁺ release, and the Na⁺/K⁺ pump in rhythmic bursting generated under different conditions. We show that a heterogeneous population of excitatory neurons can operate in different oscillatory regimes with bursting dependent on I_NaP and/or I_CAN, or independent of both. We demonstrate that the operating bursting mechanism may depend on neuronal excitation, synaptic interactions within the network, and the relative expression of particular ionic currents. The existence of multiple oscillatory regimes and their state dependence demonstrated in our models may explain different rhythmic activities observed in the pre‐BötC and other brainstem/spinal cord circuits under different experimental conditions.     

Muscarinic control of the excitability of hindlimb motoneurons in chronic spinal‐transected salamanders

The excitability of spinal motoneurons (MNs) is regulated by acetylcholine via the activation of muscarinic receptors. The objective of the present study was to determine whether this cholinergic modulation of MN excitability is altered following a chronic spinal cord transection. Juvenile salamanders (Pleurodeles waltlii) were spinally transected at the mid‐trunk level, and patch‐clamp recordings from hindlimb MNs in spinal cord slices were performed 9–30 days after transection, with and without bath application of muscarine (20 μm ). Our results showed that the input–output relationship was larger in MNs recorded 2 weeks after spinal transection than in MNs recorded 3–4 weeks after spinal transection. They further revealed that muscarine increased both the gain of MNs and the proportion of MNs that could exhibit plateau potentials and afterdischarges, whereas it decreased the amplitude of the medium afterhypolarizing potential. Moreover, muscarine had no effect on the hyperpolarization‐activated cation current (I_h), whereas it increased the inward rectifying K⁺ current (I_Kir) in MNs recorded ≥ 2 weeks after spinal transection. We conclude that following chronic spinal cord injury, the muscarinic modulation of some intrinsic properties of MNs previously reported in acute spinal‐transected animals [ S. Chevallier et al. (2006) The Journal of Physiology, 570 , 525–540] was preserved, whereas that of other intrinsic properties of MNs was suppressed, either transiently (I_Kir) or definitively (I_h). These alterations in muscarinic modulation of MN excitability may contribute to the spontaneous recovery of locomotion displayed in long‐term chronic spinal‐transected salamanders.     

h channel-dependent deficit of theta oscillation resonance and phase shift in temporal lobe epilepsy

I_h tunes hippocampal CA1 pyramidal cell dendrites to optimally respond to theta inputs (4–12 Hz), and provides a negative time delay to theta inputs. Decreased I_h activity, as seen in experimental temporal lobe epilepsy (TLE), could significantly alter the response of dendrites to theta inputs. Here we report a progressive erosion of theta resonance and phase lead in pyramidal cell dendrites during epileptogenesis in a rat model of TLE. These alterations were due to decreased I_h availability, via a decline in HCN1/HCN2 subunit expression resulting in decreased h currents, and altered kinetics of the residual channels. This acquired HCN channelopathy thus compromises temporal coding and tuning to theta inputs in pyramidal cell dendrites. Decreased theta resonance in vitro also correlated with a reduction in theta frequency and power in vivo. We suggest that the neuronal/circuitry changes associated with TLE, including altered I_h-dependent inductive mechanisms, can disrupt hippocampal theta function.     

Two distinct types of depolarizing afterpotentials are differentially expressed in stellate and pyramidal‐like neurons of entorhinal‐cortex layer II

Two types of principal neurons, stellate cells and pyramidal‐like cells, are found in medial entorhinal‐cortex (mEC) layer II, and are believed to represent two distinct channels of information processing and transmission in the entorhinal cortex–hippocampus network. In this study, we found that depolarizing afterpotentials (DAPs) that follow single action potentials (APs) evoked from various levels of holding membrane voltage (V_h) show distinct properties in the two cells types. In both, an evident DAP followed the AP at near‐threshold V_h levels, and was accompanied by an enhancement of excitability and spike‐timing precision. This DAP was sensitive to voltage‐gated Na⁺‐channel block with TTx, but not to partial removal of extracellular Ca²⁺. Application of 5‐μM anandamide, which inhibited the resurgent and persistent Na⁺‐current components in a relatively selective way, significantly reduced the amplitude of this particular DAP while exerting poor effects on the foregoing AP. In the presence of background hyperpolarization, DAPs showed an opposite behavior in the two cell types, as in stellate cells they became even more prominent, whereas in pyramidal‐like cells their amplitude was markedly reduced. The DAP observed in stellate cells under this condition was strongly inhibited by partial extracellular‐Ca²⁺ removal, and was sensitive to the low‐voltage‐activated Ca²⁺‐channel blocker, NNC55‐0396. This Ca²⁺ dependence was not observed in the residual DAP evoked in pyramidal‐like cells from likewise negative V_h levels. These results demonstrate that two distinct mechanism of DAP generation operate in mEC layer‐II neurons, one Na⁺‐dependent and active at near‐threshold V_h levels in both stellate and‐pyramidal‐like cells, the other Ca²⁺‐dependent and only expressed by stellate cells in the presence of background membrane hyperpolarization. © 2015 Wiley Periodicals, Inc.     

Intrinsic subthreshold oscillations extend the influence of inhibitory synaptic inputs on cortical pyramidal neurons

Fast inhibitory synaptic inputs, which cause conductance changes that typically last for 10–100 ms, participate in the generation and maintenance of cortical rhythms. We show here that these fast events can have influences that outlast the duration of the synaptic potentials by interacting with subthreshold membrane potential oscillations. Inhibitory postsynaptic potentials (IPSPs) in cortical neurons in vitro shifted the oscillatory phase for several seconds. The phase shift caused by two IPSPs or two current pulses summed non‐linearly. Cholinergic neuromodulation increased the power of the oscillations and decreased the magnitude of the phase shifts. These results show that the intrinsic conductances of cortical pyramidal neurons can carry information about inhibitory inputs and can extend the integration window for synaptic input.     

Differential contributions of Ca2+‐activated K+ channels and Na+/K+‐ATPases to the generation of the slow afterhyperpolarization in CA1 pyramidal cells

In many types of CNS neurons, repetitive spiking produces a slow afterhyperpolarization (sAHP), providing sustained, intrinsically generated negative feedback to neuronal excitation. Changes in the sAHP have been implicated in learning behaviors, in cognitive decline in aging, and in epileptogenesis. Despite its importance in brain function, the mechanisms generating the sAHP are still controversial. Here we have addressed the roles of M‐type K⁺ current (I_M), Ca²⁺‐gated K⁺ currents (I_Ca(K)'s) and Na⁺/K⁺‐ATPases (NKAs) current to sAHP generation in adult rat CA1 pyramidal cells maintained at near‐physiological temperature (35 °C). No evidence for I_M contribution to the sAHP was found in these neurons. Both I_Ca(K)'s and NKA current contributed to sAHP generation, the latter being the predominant generator of the sAHP, particularly when evoked with short trains of spikes. Of the different NKA isoenzymes, α₁‐NKA played the key role, endowing the sAHP a steep voltage‐dependence. Thus normal and pathological changes in α₁‐NKA expression or function may affect cognitive processes by modulating the inhibitory efficacy of the sAHP.     

Loss of β1 accessory Na+ channel subunits causes failure of carbamazepine,but not of lacosamide,in blocking high‐frequency firing via differential effects on persistent Na+ currents

Purpose: In chronic epilepsy, a substantial proportion of up to 30% of patients remain refractory to antiepileptic drugs (AEDs). An understanding of the mechanisms of pharmacoresistance requires precise knowledge of how AEDs interact with their targets. Many commonly used AEDs act on the transient and/or the persistent components of the voltage‐gated Na⁺ current (I_NaT and I_NaP, respectively). Lacosamide (LCM) is a novel AED with a unique mode of action in that it selectively enhances slow inactivation of fast transient Na⁺ channels. Given that functional loss of accessory Na⁺ channel subunits is a feature of a number of neurologic disorders, including epilepsy, we examined the effects of LCM versus carbamazepine (CBZ) on the persistent Na⁺ current (I_NaP), in the presence and absence of accessory subunits within the channel complex. Methods: Using patch‐clamp recordings in intact hippocampal CA1 neurons of Scn1b null mice, I_NaP was recorded using slow voltage ramps. Application of 100 μm CBZ or 300 μm LCM reduced the maximal I_NaP conductance in both wild‐type and control mice. Key Findings: As shown previously by our group in Scn1b null mice, CBZ induced a paradoxical increase of I_NaP conductance in the subthreshold voltage range, resulting in an ineffective block of repetitive firing in Scn1b null neurons. In contrast, LCM did not exhibit such a paradoxical increase, and accordingly maintained efficacy in blocking repetitive firing in Scn1b null mice. Significance: These results suggest that the novel anticonvulsant LCM maintains activity in the presence of impaired Na⁺ channel β₁ subunit expression and thus may offer an improved efficacy profile compared with CBZ in diseases associated with an impaired expression of β sub‐units as observed in epilepsy.