Afterhyperpolarization Research Articles

Learning enhances intrinsic excitability in a subset of lateral amygdala neurons.

Learning-induced modulation of neuronal intrinsic excitability is a metaplasticity mechanism that can impact the acquisition of new memories. Although the amygdala is important for emotional learning and other behaviors, including fear and anxiety, whether learning alters intrinsic excitability within the amygdala has received very little attention. Fear conditioning was combined with intracellular recordings to investigate the effects of learning on the intrinsic excitability of lateral amygdala (LA) neurons. To assess time-dependent changes, brain slices were prepared either immediately or 24-h post-conditioning. Fear conditioning significantly enhanced excitability of LA neurons, as evidenced by both decreased afterhyperpolarization (AHP) and increased neuronal firing. These changes were time-dependent such that reduced AHPs were evident at both time points whereas increased neuronal firing was only observed at the later (24-h) time point. Moreover, these changes occurred within a subset (32%) of LA neurons. Previous work also demonstrated that learning-related changes in synaptic plasticity are also evident in less than one-third of amygdala neurons, suggesting that the neurons undergoing intrinsic plasticity may be critical for fear memory. These data may be clinically relevant as enhanced LA excitability following fear learning could influence future amygdala-dependent behaviors.

Complementary functions of SK and Kv7/M potassium channels in excitability control and synaptic integration in rat hippocampal dentate granule cells

The dentate granule cells (DGCs) form the most numerous neuron population of the hippocampal memory system, and its gateway for cortical input. Yet, we have only limited knowledge of the intrinsic membrane properties that shape their responses. Since SK and Kv7/M potassium channels are key mechanisms of neuronal spiking and excitability control, afterhyperpolarizations (AHPs) and synaptic integration, we studied their functions in DGCs. The specific SK channel blockers apamin or scyllatoxin increased spike frequency (excitability), reduced early spike frequency adaptation, fully blocked the medium-duration AHP (mAHP) after a single spike or spike train, and increased postsynaptic EPSP summation after spiking, but had no effect on input resistance (Rinput) or spike threshold. In contrast, blockade of Kv7/M channels by XE991 increased Rinput, lowered the spike threshold, and increased excitability, postsynaptic EPSP summation, and EPSP-spike coupling, but only slightly reduced mAHP after spike trains (and not after single spikes). The SK and Kv7/M channel openers 1-EBIO and retigabine, respectively, had effects opposite to the blockers. Computational modelling reproduced many of these effects. We conclude that SK and Kv7/M channels have complementary roles in DGCs. These mechanisms may be important for the dentate network function, as CA3 neurons can be activated or inhibition recruited depending on DGC firing rate.

Kv2 dysfunction after peripheral axotomy enhances sensory neuron responsiveness to sustained input

Peripheral nerve injuries caused by trauma are associated with increased sensory neuron excitability and debilitating chronic pain symptoms. Axotomy-induced alterations in the function of ion channels are thought to largely underlie the pathophysiology of these phenotypes. Here, we characterise the mRNA distribution of Kv2 family members in rat dorsal root ganglia (DRG) and describe a link between Kv2 function and modulation of sensory neuron excitability. Kv2.1 and Kv2.2 were amply expressed in cells of all sizes, being particularly abundant in medium-large neurons also immunoreactive for neurofilament-200. Peripheral axotomy led to a rapid, robust and long-lasting transcriptional Kv2 downregulation in the DRG, correlated with the onset of mechanical and thermal hypersensitivity. The consequences of Kv2 loss-of-function were subsequently investigated in myelinated neurons using intracellular recordings on ex vivo DRG preparations. In naïve neurons, pharmacological Kv2.1/Kv2.2 inhibition by stromatoxin-1 (ScTx) resulted in shortening of action potential (AP) after-hyperpolarization (AHP). In contrast, ScTx application on axotomized neurons did not alter AHP duration, consistent with the injury-induced Kv2 downregulation. In accordance with a shortened AHP, ScTx treatment also reduced the refractory period and improved AP conduction to the cell soma during high frequency stimulation. These results suggest that Kv2 downregulation following traumatic nerve lesion facilitates greater fidelity of repetitive firing during prolonged input and thus normal Kv2 function is postulated to limit neuronal excitability. In summary, we have profiled Kv2 expression in sensory neurons and provide evidence for the contribution of Kv2 dysfunction in the generation of hyperexcitable phenotypes encountered in chronic pain states.

Concomitant changes in afterhyperpolarization and twitch following repetitive stimulation of fast motoneurones and motor units

The study aimed at determining changes in a course of motoneuronal afterhyperpolarization (AHP) and in contractile twitches of motor units (MUs) during activity evoked by increasing number of stimuli (from 1 to 5), at short interspike intervals (5 ms). The stimulation was applied antidromically to spinal motoneurones or to isolated axons of MUs of the medial gastrocnemius muscle within two separate series of experiments on anesthetized rats. Alterations in the amplitude and time parameters of the AHP of successive spikes were compared to changes in force and time course of successive twitches obtained by mathematical subtraction of tetanic contractions evoked by one to five stimuli. The extent of changes of the studied parameters depended on a number of applied stimuli. The maximal modulation of the AHP and twitch parameters (a prolongation and an increase in the AHP and twitch amplitudes) was typically observed after the second pulse, while higher number of pulses at the same frequency did not induce so prominent changes. One may conclude that changes observed in parameters of action potentials of motoneurons are concomitant to changes in contractile properties of MU twitches. This suggests that both modulations of the AHP and twitch parameters reflect mechanisms leading to force development at the beginning of MU activity.

Motoneurone afterhyperpolarisation time-course following stroke

ObjectiveOur aim was to investigate any changes in the estimated time-course of the afterhyperpolarisation (AHP) in motoneurones innervating the tibialis anterior following stroke, with a secondary objective to compare the results from two different AHP estimation techniques. MethodsMotor units from tibialis anterior on the paretic and non-paretic sides of 15 subjects with chronic stroke were recorded using intramuscular electrodes during voluntary isometric contraction. Participants varied the motor unit firing rate from its lowest rate to approximately 10Hz. The AHP duration was estimated using the interval death rate (IDR) and transition point methods. ResultsThe AHP decay time-constant was significantly different between sides (paretic: 41.7±8.5ms, non-paretic: 36.2±6.4ms). Additionally, the paretic AHP time-constant was significantly longer in participants with low motor recovery (45.9±9.1ms) than with high motor recovery (39.3±10.0ms) as measured by CMSA score. The AHP estimates from the two techniques were correlated (r=0.78). ConclusionsThe AHP time-course prolongation on the paretic side of people with chronic stroke is more pronounced in people with low motor recovery. SignificanceChanges in the motoneurone AHP time course post-stroke were related to muscle function and may play a role in the commonly-observed reduction of motor unit discharge rate during voluntary contractions following stroke.

Discharge regularity in the turtle posterior crista: comparisons between experiment and theory

Intra-axonal recordings were made from bouton fibers near their termination in the turtle posterior crista. Spike discharge, miniature excitatory postsynaptic potentials (mEPSPs), and afterhyperpolarizations (AHPs) were monitored during resting activity in both regularly and irregularly discharging units. Quantal size (qsize) and quantal rate (qrate) were estimated by shot-noise theory. Theoretically, the ratio, σV/(dμV/dt), between synaptic noise (σV) and the slope of the mean voltage trajectory (dμV/dt) near threshold crossing should determine discharge regularity. AHPs are deeper and more prolonged in regular units; as a result, dμV/dt is larger, the more regular the discharge. The qsize is larger and qrate smaller in irregular units; these oppositely directed trends lead to little variation in σV with discharge regularity. Of the two variables, dμV/dt is much more influential than the nearly constant σV in determining regularity. Sinusoidal canal-duct indentations at 0.3 Hz led to modulations in spike discharge and synaptic voltage. Gain, the ratio between the amplitudes of the two modulations, and phase leads re indentation of both modulations are larger in irregular units. Gain variations parallel the sensitivity of the postsynaptic spike encoder, the set of conductances that converts synaptic input into spike discharge. Phase variations reflect both synaptic inputs to the encoder and postsynaptic processes. Experimental data were interpreted using a stochastic integrate-and-fire model. Advantages of an irregular discharge include an enhanced encoder gain and the prevention of nonlinear phase locking. Regular and irregular units are more efficient, respectively, in the encoding of low- and high-frequency head rotations, respectively.

Contribution of dopamine d1/5 receptor modulation of post-spike/burst afterhyperpolarization to enhance neuronal excitability of layer v pyramidal neurons in prepubertal rat prefrontal cortex.

Dopamine (DA) receptors in the prefrontal cortex (PFC) modulate both synaptic and intrinsic plasticity that may contribute to cognitive processing. However, the ionic basis underlying DA actions to enhance neuronal plasticity in PFC remains ill-defined. Using whole-cell patch-clamp recordings in layer V-VI pyramidal cells in prepubertal rat PFC, we showed that DA, via activation of D1/5, but not D2/3/4, receptors suppress a Ca2+-dependent, apamin-sensitive K+ channel that mediates post-spike/burst afterhyperpolarization (AHP) to enhance neuronal excitability of PFC neurons. This inhibition is not dependent on HCN channels. The D1/5 receptor activation also enhanced an afterdepolarizing potential (ADP) that follows the AHP. Additional single-spike analyses revealed that DA or D1/5 receptor activation suppressed the apamin-sensitive post-spike mAHP, further contributing to the increase in evoked spike firing to enhance the neuronal excitability. Taken together, the D1/5 receptor modulates intrinsic mechanisms that amplify a long depolarizing input to sustain spike firing outputs in pyramidal PFC neurons.

A Sodium-Pump-Mediated Afterhyperpolarization in Pyramidal Neurons

The sodium-potassium ATPase (i.e., the "sodium pump") plays a central role in maintaining ionic homeostasis in all cells. Although the sodium pump is intrinsically electrogenic and responsive to dynamic changes in intracellular sodium concentration, its role in regulating neuronal excitability remains unclear. Here we describe a physiological role for the sodium pump in regulating the excitability of mouse neocortical layer 5 and hippocampal CA1 pyramidal neurons. Trains of action potentials produced long-lasting (∼20 s) afterhyperpolarizations (AHPs) that were insensitive to blockade of voltage-gated calcium channels or chelation of intracellular calcium, but were blocked by tetrodotoxin, ouabain, or the removal of extracellular potassium. Correspondingly, the AHP time course was similar to the decay of activity-induced increases in intracellular sodium, whereas intracellular calcium decayed at much faster rates. To determine whether physiological patterns of activity engage the sodium pump, we replayed in vitro a place-specific burst of 15 action potentials recorded originally in vivo in a CA1 "place cell" as the animal traversed the associated place field. In both layer 5 and CA1 pyramidal neurons, this "place cell train" generated small, long-lasting AHPs capable of reducing neuronal excitability for many seconds. Place-cell-train-induced AHPs were blocked by ouabain or removal of extracellular potassium, but not by intracellular calcium chelation. Finally, we found calcium contributions to the AHP to be temperature dependent: prominent at room temperature, but largely absent at 35°C. Our results demonstrate a previously unappreciated role for the sodium-potassium ATPase in regulating the excitability of neocortical and hippocampal pyramidal neurons.

Modulation of the Intrinsic Properties of Motoneurons by Serotonin

Serotonin (5-HT) is one of the main transmitters in the nervous system. Serotonergic neurons in the raphe nuclei in the brainstem innervate most parts of the central nervous system including motoneurons in the spinal cord and brainstem. This review will focus on the modulatory role that 5-HT exerts on motoneurons and its physiological consequences. The somato-dendritic compartments of motoneurons are densely innervated by serotonergic synaptic boutons and several receptors are expressed in the membrane of motoneurons including 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C and 5-HT5A. The activation of serotonergic receptors induces a general increase of the excitability of motoneurons through the modulation of several classes of ion channels. 5-HT depolarizes motoneurons towards the threshold for action potentials by inhibiting leak conductances and promoting a hyperpolarization activated cationic current. At the same time, 5-HT increases the firing frequency by inhibiting the small Ca2+ activated K+ conductance (SK) responsible for the medium afterhyperpolarization (AHP) following action potentials. 5-HT also promotes persistent inward currents mediated by voltage sensitive Ca2+ and Na+ conductances, producing a sustained depolarization and an amplification of synaptic inputs. Under pathological conditions, such as after a spinal cord injury, the promotion of persistent inward currents by serotonin and/or the overexpression of autoactive serotonergic receptors may contribute to motoneuronal excitability, muscle spasms and spasticity and hence, impairment of stereotyped motor behaviors such as locomotion, ejaculation and micturition.

Bifidobacterium longum NCC3001 inhibits AH neuron excitability

Bifidobacterium longum (B. longum) NCC3001 can affect behavior and brain biochemistry, but identification of the cellular targets needs further investigation. Our hypothesis was that the communication with the brain might start with action on enteric sensory neurons. Ileal segments from adult mice were used to create a longitudinal muscle-myenteric-plexus preparation to expose sensory after-hyperpolarizing (AH) neurons in the myenteric plexus to allow access with microelectrodes. The intrinsic excitability of AH neurons was tested in response to the perfusion of conditioned media (B.longum culture supernatant) or unconditioned media (growth medium, MRS). B. longum conditioned medium significantly reduced the excitability of AH neurons compared to perfusion with the unconditioned medium. Specifically, a reduction was seen in the number of action potentials fired per depolarizing test pulse, the instantaneous and time-dependent input resistances and the magnitude of the hyperpolarization-activated cationic current (Ih ). The probiotic B.longum reduces excitability of AH sensory neurons likely via opening of potassium channels and closing of hyperpolarization-activated cation channels.

Exercise Training after Spinal Cord Injury Selectively Alters Synaptic Properties in Neurons in Adult Mouse Spinal Cord

Following spinal cord injury (SCI), anatomical changes such as axonal sprouting occur within weeks in the vicinity of the injury. Exercise training enhances axon sprouting; however, the exact mechanisms that mediate exercised-induced plasticity are unknown. We studied the effects of exercise training after SCI on the intrinsic and synaptic properties of spinal neurons in the immediate vicinity (<2 segments) of the SCI. Male mice (C57BL/6, 9-10 weeks old) received a spinal hemisection (T10) and after 1 week of recovery, they were randomized to trained (treadmill exercise for 3 weeks) and untrained (no exercise) groups. After 3 weeks, mice were killed and horizontal spinal cord slices (T6-L1, 250 μm thick) were prepared for visually guided whole cell patch clamp recording. Intrinsic properties, including resting membrane potential, input resistance, rheobase current, action potential (AP) threshold and after-hyperpolarization (AHP) amplitude were similar in neurons from trained and untrained mice (n=67 and 70 neurons, respectively). Neurons could be grouped into four categories based on their AP discharge during depolarizing current injection; the proportions of tonic firing, initial bursting, single spiking, and delayed firing neurons were similar in trained and untrained mice. The properties of spontaneous excitatory synaptic currents (sEPSCs) did not differ in trained and untrained animals. In contrast, evoked excitatory synaptic currents recorded after dorsal column stimulation were markedly increased in trained animals (peak amplitude 78.9±17.5 vs. 42.2±6.8 pA; charge 1054±376 vs. 348±75 pA·ms). These data suggest that 3 weeks of treadmill exercise does not affect the intrinsic properties of spinal neurons after SCI; however, excitatory synaptic drive from dorsal column pathways, such as the corticospinal tract, is enhanced.

Chemosensitive neurons in the retrotrapezoid nucleus (RTN) express SK channels with low Ca2+ affinity

Chemosensitive RTN neurons regulate breathing in response to changes in tissue CO2/H+. despite the importance of these cells, little is known regarding molecular determinants of their intrinsic excitability. We have recently determined that RTN chemoreceptors express Ca2+‐activated small conductance K+ (SK) channels, however, the role of these channels in chemoreceptor function is unknown. Here, we use electrophysiological and computational approaches to explore SK channel function in RTN neurons. In brain slices (300 μm thick) from rat pups (P7–12), cell‐attached recordings of membrane potential show that bath application of apamin (selective SK channel blocker) decreased amplitude of the after hyperpolarization (AHP) evoked by depolarizing current injection but did not affect baseline activity. Based on computer simulations, we predict that under baseline conditions and high Ca2+ pump activity, [Ca2+]i should be sufficient to activate SK channels with a typical Ca2+affinity of &lt; 1μM. Therefore, we predict that RTN neurons express SK channels with low Ca2+ affinity possibly due to high casein kinase‐2 (CK2) activity. Consistent with this possibility, we found that TBB (a selective CK2 inhibitor) eliminated spontaneous activity of RTN neurons as expected for activation of a K+ conductance. These results suggest that the contribution of SK channels to activity of RTN neurons is regulated by CK2 activity.

Learning increases intrinsic excitability of hippocampal interneurons.

Learning-related intrinsic excitability changes of pyramidal neurons via modulation of the postburst afterhyperpolarization (AHP) have been repeatedly demonstrated in multiple brain regions (especially the hippocampus), after a variety of learning tasks, and in multiple species. While exciting and important, the changes in pyramidal neurons are only a part of the neural circuitry involved in successful learning. For a more complete picture of the dynamic learning-related changes in the neural network, changes in inhibitory circuitry must also be systematically examined and characterized. Here we show in young adult rats and mice that learning the hippocampus-dependent trace eyeblink conditioning task induces enhanced inhibition onto CA1 pyramidal neurons mediated, in part, by an increase in intrinsic excitability of somatostatin-positive inhibitory neurons (SOMs). Furthermore, both CA1 pyramidal and SOM interneurons shared a common cellular mechanism (reduction in SK channel-mediated AHP) that led to the learning-induced increased intrinsic excitability.

Further studies on bis-charged tetraazacyclophanes as potent inhibitors of small conductance Ca2+-activated K+ channels

Previously, quinolinium-based tetraazacyclophanes, such as UCL 1684 and UCL 1848, have been shown to be extraordinarily sensitive to changes in chemical structure (especially to the size of the cyclophane system) with respect to activity as potent non-peptidic blockers of the small conductance Ca2+-activated K+ ion channels (SKCa). The present work has sought to optimize the structure of the linking chains in UCL 1848. We report the synthesis and SKCa channel-blocking activity of 29 analogues of UCL 1848 in which the central CH2 of UCL 1848 is replaced by other groups X or Y = O, S, CF2, CO, CHOH, CC, CHCH, CHMe to explore whether subtle changes in bond length or flexibility can improve potency still further. The possibility of improving potency by introducing ring substituents has also been explored by synthesizing and testing 25 analogues of UCL 1684 and UCL 1848 with substituents (NO2, NH2, CF3, F, Cl, CH3, OCH3, OCF3, OH) in the 5, 6 or 7 positions of the aminoquinolinium rings. As in our earlier work, each compound was assayed for inhibition of the afterhyperpolarization (AHP) in rat sympathetic neurons, an action mediated by the SK3 subtype of the SKCa channel. One of the new compounds (39, R7 = Cl, UCL 2053) is twice as potent as UCL 1848 and UCL 1684: seven are comparable in activity.

Identity, expression and functional role of the sodium-activated potassium current in vestibular ganglion afferent neurons

Vestibular afferent neurons (VANs) transmit information from the vestibular end organs to the central nuclei. This information is encoded within the firing pattern of these cells and is heavily influenced by the K+ conductances expressed by vestibular neurons. In the present study, we describe the presence of a previously unidentified Na+-activated K+ conductance (KNa) in these cells. We observed that the blocking of Na+ channels by tetrodotoxin (TTX) or the substitution of choline for Na+ in the extracellular solution during voltage clamp pulses resulted in the reduction of a sustained outward current that was dependent on the Na+ current. Furthermore, increases in the intracellular concentration of Na+ that were made by blocking the Na+/K+ ATPase with ouabain increased the amplitude of the outward current, and reduction of the intracellular Cl− concentration reduced the TTX-sensitive outward current. The substitution of Li+ for Na+ in the extracellular solution significantly reduced the amplitude of the outward current in voltage clamp pulses and decreased the afterhyperpolarization (AHP) of the action potentials in current clamp experiments. These electrophysiological results are consistent with the presence of mRNA transcripts for the KNa subunits Slick and Slack in the vestibular ganglia and in the sensory epithelium, which were detected using reverse-transcription polymerase chain reaction (RT-PCR). These results are also consistent with the immunolabeling of Slick and Slack protein in isolated vestibular neurons, in the vestibular ganglion and in the vestibular sensory epithelium. These results indicate that KNa channels are expressed in VANs and in their terminals. Furthermore, these data indicate that these channels may contribute to the firing pattern of vestibular neurons.

Biophysical properties and computational modeling of calcium spikes in serotonergic neurons of the dorsal raphe nucleus

Serotonergic neurons of the dorsal raphe nuclei, with their extensive innervation of nearly the whole brain have important modulatory effects on many cognitive and physiological processes. They play important roles in clinical depression and other psychiatric disorders. In order to quantify the effects of serotonergic transmission on target cells it is desirable to construct computational models and to this end these it is necessary to have details of the biophysical and spike properties of the serotonergic neurons. Here several basic properties are reviewed with data from several studies since the 1960s to the present. The quantities included are input resistance, resting membrane potential, membrane time constant, firing rate, spike duration, spike and afterhyperpolarization (AHP) amplitude, spike threshold, cell capacitance, soma and somadendritic areas. The action potentials of these cells are normally triggered by a combination of sodium and calcium currents which may result in autonomous pacemaker activity. We here analyse the mechanisms of high-threshold calcium spikes which have been demonstrated in these cells the presence of TTX (tetrodotoxin). The parameters for calcium dynamics required to give calcium spikes are quite different from those for regular spiking which suggests the involvement of restricted parts of the soma-dendritic surface as has been found, for example, in hippocampal neurons.

Delayed depolarization and firing behavior of human motoneurons during voluntary muscle contractions.

The firing behavior of motoneurons is governed by the interaction between the intrinsic properties of motoneurons and the synaptic inputs that they receive. In particular, long-lasting after-hyperpolarization (AHP) following each motoneuron spike and thus decreasing motoneuron excitability immediately after spike was found to be a key mechanism in controlling of interspike interval (ISI) duration (Eccles et al., 1958; Kernell, 1965). As a result, motoneurons commonly fire single discharges at rather low firing rates, especially during gentle voluntary muscle contractions and postural tasks. However, some motoneurons, under conditions of weak synaptic drive, can fire double discharges (doublets) with very short intradoublet ISIs (up to a few ms). Each doublet is commonly followed by a prolonged post-doublet (interdoublet) ISI resulting from the AHP summation (Calvin and Schwindt, 1972). Two types of doublets have been observed: single and repetitive ones. Single doublets have been reported many times in cat and human motoneurons (e.g., Eccles and Hoff, 1932; Hoff and Grant, 1944; Denslow, 1948; Calvin and Schwindt, 1972; Kudina, 1974; Kudina and Churikova, 1990; Kirkwood and Munson, 1996; Piotrkiewicz et al., 2008; Stephenson and Maluf, 2010). Repetitive doublets have also been demonstrated in some of the reports above, but as a rule by the way; and only a few studies have directly addressed this topic (Bawa and Calancie, 1983; Kudina and Alexeeva, 1992; Kudina and Andreeva, 2010). However, a number of questions are still unanswered, in particular the question of whether there are certain muscles and (or) certain motoneurons for which repetitive doublet firing is likely to appear. This question will be taken up below based on an analysis of doublet firing in different limb and trunk muscles in healthy humans. With regard to the origin of this surprising firing, currently, the short delayed depolarization (DD) appearing as a “hump” on the falling phase of an action potential, preceding the AHP (Granit et al., 1963; Kernell, 1964; Nelson and Burke, 1967; Kernell, 2006) and thus shortly increasing MN excitability is widely accepted as the mechanism responsible for single doublets in cat (Calvin and Schwindt, 1972; Kirkwood and Munson, 1996; see also Kernell, 2006), and human motoneurons (Kudina, 1974; Bawa and Calancie, 1983; Kudina and Alexeeva, 1992; Bawa and Lemon, 1993; Garland and Griffin, 1999; Piotrkiewicz et al., 2008; Stephenson and Maluf, 2010). As to the origin of repetitive doublets, the question still remains open. At first sight, one could assume that they have the same underlying mechanism like single doublets. However, as known from findings by Granit et al. (1963) and Calvin (1975), in cat motoneurons, the hump-DD changes systematically during rhythmic firing evoked by intracellular depolarization, becoming smaller with each successive spike. Therefore, as may be expected, in firing motoneurons the DD can reach the threshold only occasionally and generate single doublets only. Consequently, it might be suggested that the DD alone can hardly play a pivotal role in producing repetitive doublets. In our recent studies (Kudina and Andreeva, 2010, 2013), we hypothesized that the mechanism underlying repetitive doublet firing in human motoneurons during voluntary muscle contraction is complex, including the hump-DD as the primary determinant that possibly becomes persistent due to a plateau potential probably activated in parallel with a common synaptic input. The assumption about a plateau potential role in repetitive doublet mechanisms was inferred from the comparison between essential characteristics of human motor unit (MU) repetitive doublet firing and properties of cat motoneuron firing in the presence of a plateau potential (e.g., Conway et al., 1988). If this assumption is true, then the question arises what are the DD characteristics which become persistent during repetitive doublet firing. The question will be considered below.

Dynamics of action potential firing in electrically connected striatal fast-spiking interneurons

Fast-spiking interneurons (FSIs) play a central role in organizing the output of striatal neural circuits, yet functional interactions between these cells are still largely unknown. Here we investigated the interplay of action potential (AP) firing between electrically connected pairs of identified FSIs in mouse striatal slices. In addition to a loose coordination of firing activity mediated by membrane potential coupling, gap junctions (GJ) induced a frequency-dependent inhibition of spike discharge in coupled cells. At relatively low firing rates (2–20 Hz), some APs were tightly synchronized whereas others were inhibited. However, burst firing at intermediate frequencies (25–60 Hz) mostly induced spike inhibition, while at frequencies >50–60 Hz FSI pairs tended to synchronize. Spike silencing occurred even in the absence of GABAergic synapses or persisted after a complete block of GABAA receptors. Pharmacological suppression of presynaptic spike afterhyperpolarization (AHP) caused postsynaptic spikelets to become more prone to trigger spikes at near-threshold potentials, leading to a mostly synchronous firing activity. The complex pattern of functional coordination mediated by GJ endows FSIs with peculiar dynamic properties that may be critical in controlling striatal-dependent behavior.

Double discharges in human soleus muscle.

Double discharges (doublets) were recorded from human soleus (SOL), where they have never been reported before. The data analyzed in this study were collected from 12 healthy volunteers. The subjects were recruited for other studies, concerning: (1) estimation of motoneurons’ (MNs) afterhyperpolarization (AHP) duration and (2) analysis of motor unit responses to nerve stimulation, and were not trained to voluntarily evoke doublets. The majority of intradoublet intervals fell into the commonly accepted range 2–20 ms. However, two SOL MNs from one presented exceptional doublets of intradoublet interval about 37 ms. This interval was virtually identical with the interval between second and third discharge in the few triplets recorded from another subject. It is hypothesized that triplets are generated by the delayed depolarization with the second narrow hump, which is the same as the hump responsible for exceptional doublets.

Extracellular Ca2 + fluctuations in vivo affect afterhyperpolarization potential and modify firing patterns of neocortical neurons

Neocortical neurons can be classified in four major electrophysiological types according to their pattern of discharge: regular-spiking (RS), intrinsically-bursting (IB), fast-rhythmic-bursting (FRB), and fast-spiking (FS). Previously, we have shown that these firing patterns are not fixed and can change as a function of membrane potential and states of vigilance. Other studies have reported that extracellular calcium concentration ([Ca2+]o) fluctuates as a function of the phase of the cortical slow oscillation. In the present study we investigated how spontaneous and induced changes in [Ca2+]o affect the properties of action potentials (APs) and firing patterns in cortical neurons in vivo. Intracellular recordings were performed in cats anesthetized with ketamine–xylazine during spontaneous [Ca2+]o fluctuation and while changing [Ca2+]o with reverse microdialysis. When [Ca2+]o fluctuated spontaneously according to the phase of the slow oscillation, we found an increase of the firing threshold and a decrease of the afterhyperpolarization (AHP) amplitude during the depolarizing (active, up) phase of the slow oscillation and some neurons also changed their firing pattern as compared with the hyperpolarizing (silent, down) phase. Induced changes in [Ca2+]o significantly affected the AP properties in all neurons. The AHP amplitude was increased in high calcium conditions and decreased in low calcium conditions, in particular the earliest components. Modulation of spike AHP resulted in notable modulation of intrinsic firing pattern and some RS neurons revealed burst firing when [Ca2+]o was decreased. We also found an increase in AHP amplitude in high [Ca2+]o with in vitro preparation. We suggest that during spontaneous network oscillations in vivo, the dynamic changes of firing patterns depend partially on fluctuations of the [Ca2+]o.