Reduced Action Potential Amplitude Research Articles

Reduced plakoglobin increases the risk of sodium current defects and atrial conduction abnormalities in response to androgenic anabolic steroid abuse.

Androgenic anabolic steroids (AAS) are commonly abused by young men. Male sex and increased AAS levels are associated with earlier and more severe manifestation of common cardiac conditions, such as atrial fibrillation, and rare ones, such as arrhythmogenic right ventricular cardiomyopathy (ARVC). Clinical observations suggest a potential atrial involvement in ARVC. Arrhythmogenic right ventricular cardiomyopathy is caused by desmosomal gene defects, including reduced plakoglobin expression. Here, we analysed clinical records from 146 ARVC patients to identify that ARVC is more common in males than females. Patients with ARVC also had an increased incidence of atrial arrhythmias and Pwave changes. To study desmosomal vulnerability and the effects of AAS on the atria, young adult male mice, heterozygously deficient for plakoglobin (Plako+/-), and wild type (WT) littermates were chronically exposed to 5α-dihydrotestosterone (DHT) or placebo. The DHT increased atrial expression of pro-hypertrophic, fibrotic and inflammatory transcripts. In mice with reduced plakoglobin, DHT exaggerated Pwave abnormalities, atrial conduction slowing, sodium current depletion, action potential amplitude reduction and the fall in action potential depolarization rate. Super-resolution microscopy revealed a decrease in NaV1.5membrane clustering in Plako+/- atrial cardiomyocytes after DHT exposure. In summary, AAS combined with plakoglobin deficiency cause pathological atrial electrical remodelling in young male hearts. Male sex is likely to increase the risk of atrial arrhythmia, particularly in those with desmosomal gene variants. This risk is likely to be exaggerated further by AAS use. KEY POINTS: Androgenic male sex hormones, such as testosterone,might increase the risk of atrial fibrillation in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), which is often caused by desmosomal gene defects (e.g. reduced plakoglobin expression). In this study, we observed a significantly higher proportion of males who had ARVC compared with females, and atrial arrhythmias and Pwave changes represented a common observation in advanced ARVC stages. In mice with reduced plakoglobin expression, chronic administration of 5α-dihydrotestosterone led to Pwave abnormalities, atrial conduction slowing, sodium current depletion and a decrease in membrane-localized NaV1.5 clusters. 5α-Dihydrotestosterone, therefore, represents a stimulus aggravating the pro-arrhythmic phenotype in carriers of desmosomal mutations and can affect atrial electrical function.

Are Electrocochleographic Changes an Early Sign of Cochlear Synaptopathy? A Prospective Study in Tinnitus Patients with Normal Hearing.

The mechanism of tinnitus accompanied by a normal audiogram remains elusive. This study aimed to investigate evidence of primary neural degeneration, also known as cochlear synaptopathy, in tinnitus patients with normal hearing thresholds. We analyzed the differences in electrocochleography (ECochG) measurements between normal-hearing subjects with and without tinnitus. Forty-five subjects were enrolled in this study: 21 were in the tinnitus group, defined by chronic tinnitus of over two months’ duration with normal audiometric thresholds, and 24 were in the control group, defined by a lack of tinnitus complaints. Electrocochleograms were evoked by 1, 4, 6, and 8 kHz alternating-polarity tone bursts at sound pressure levels (SPLs) of 90–110 dB. The tinnitus group had smaller action potential (AP) amplitudes than the control group for 1, 4, 6, and 8 kHz tone bursts and showed significant amplitude reduction at 1 kHz 110 dB SPL (p < 0.01), 1 kHz 90 dB SPL (p < 0.05), and 4 kHz 110 dB SPL (p < 0.05). There were no significant differences in the summating potential/action potential (SP/AP) amplitude ratios across the four tested frequencies. A trend of reduced AP amplitudes was found in the tinnitus group, supporting the hypothesis that tinnitus might be associated with primary neural degeneration.

The novel persistent sodium current inhibitor PRAX-562 has potent anticonvulsant activity with improved protective index relative to standard of care sodium channel blockers.

ObjectiveThis study investigates the effects of PRAX‐562 on sodium current (INa), intrinsic neuronal excitability, and protection from evoked seizures to determine whether a preferential persistent INa inhibitor would exhibit improved preclinical efficacy and tolerability compared to two standard voltage‐gated sodium channel (NaV) blockers.MethodsInhibition of INa was characterized using patch clamp analysis. The effect on intrinsic excitability was measured using evoked action potentials recorded from hippocampal CA1 pyramidal neurons in mouse brain slices. Anticonvulsant activity was evaluated using the maximal electroshock seizure (MES) model, and tolerability was assessed by measuring spontaneous locomotor activity (sLMA).ResultsPRAX‐562 potently and preferentially inhibited persistent INa induced by ATX‐II or the SCN8A mutation N1768D (half‐maximal inhibitory concentration [IC50] = 141 and 75 nmol·L–1, respectively) relative to peak INa tonic/resting block (60× preference). PRAX‐562 also exhibited potent use‐dependent block (31× preference to tonic block). This profile is considerably different from standard NaV blockers, including carbamazepine (CBZ; persistent INa IC50 = 77 500 nmol·L–1, preference ratios of 30× [tonic block], less use‐dependent block observed at various frequencies). In contrast to CBZ, PRAX‐562 reduced neuronal intrinsic excitability with only a minor reduction in action potential amplitude. PRAX‐562 (10 mg/kg po) completely prevented evoked seizures without affecting sLMA (MES unbound brain half‐maximal efficacious concentration = 4.3 nmol·L–1, sLMA half‐maximal tolerated concentration = 69.7 nmol·L–1, protective index [PI] = 16×). In contrast, CBZ and lamotrigine (LTG) had PIs of approximately 5.5×, with significant overlap between doses that were anticonvulsant and that reduced locomotor activity.SignificancePRAX‐562 demonstrated robust preclinical anticonvulsant activity similar to CBZ but improved compared to LTG. PRAX‐562 exhibited significantly improved preclinical tolerability compared with standard NaV blockers (CBZ and LTG), potentially due to the preference for persistent INa. Preferential targeting of persistent INa may represent a differentiated therapeutic option for diseases of hyperexcitability, where standard NaV blockers have demonstrated efficacy but poor tolerability.

Lambert-Eaton Myasthenic Syndrome in Lung Cancer.

The aim is to study lung cancer with Lambert-Eaton myasthenic syndrome (LEMS) with clinical and electrical characteristics of physiology and prognosis. Fourteen LEMS patients with lung cancer were studied retrospectively. The data including demographics, clinical presentation, treatments, and prognosis from the medical records were analyzed. Lung cancer coexisting with LEMS is more common in men (10/14). The median age was 67.1 years. Eleven (78.6%) patients experienced gradual onset of disease. Most patients presented nervous system lesions prior to occult tumors. The most common symptoms reported were proximal muscle weakness (92.9%), decreased or absent tendon reflexes (50%), and autonomic dysfunction (71.4%). All the patients showed reduction in action potential amplitude after repetitive peripheral never stimulation at low frequency and increased amplitude at high frequency. LEMS usually occurs prior to lung cancer with complicated and various clinical manifestations in our centers. We should improve awareness and knowledge of such disease to shorten the diagnostic delay and lead to few misdiagnoses.

Atrial resting membrane potential confers sodium current sensitivity to propafenone, flecainide and dronedarone

BackgroundAlthough atrial fibrillation ablation is increasingly used for rhythm control therapy, antiarrhythmic drugs (AADs) are commonly used, either alone or in combination with ablation. The effectiveness of AADs is highly variable. Previous work from our group suggests that alterations in atrial resting membrane potential (RMP) induced by low Pitx2 expression could explain the variable effect of flecainide.ObjectiveThe purpose of this study was to assess whether alterations in atrial/cardiac RMP modify the effectiveness of multiple clinically used AADs.MethodsThe sodium channel blocking effects of propafenone (300 nM, 1 μM), flecainide (1 μM), and dronedarone (5 μM, 10 μM) were measured in human stem cell–derived cardiac myocytes, HEK293 expressing human NaV1.5, primary murine atrial cardiac myocytes, and murine hearts with reduced Pitx2c.ResultsA more positive atrial RMP delayed INa recovery, slowed channel inactivation, and decreased peak action potential (AP) upstroke velocity. All 3 AADs displayed enhanced sodium channel block at more positive atrial RMPs. Dronedarone was the most sensitive to changes in atrial RMP. Dronedarone caused greater reductions in AP amplitude and peak AP upstroke velocity at more positive RMPs. Dronedarone evoked greater prolongation of the atrial effective refractory period and postrepolarization refractoriness in murine Langendorff-perfused Pitx2c+/– hearts, which have a more positive RMP compared to wild type.ConclusionAtrial RMP modifies the effectiveness of several clinically used AADs. Dronedarone is more sensitive to changes in atrial RMP than flecainide or propafenone. Identifying and modifying atrial RMP may offer a novel approach to enhancing the effectiveness of AADs or personalizing AAD selection.

Interneuron Dysfunction in a New Mouse Model of SCN1A GEFS.

Advances in genome sequencing have identified over 1300 mutations in the SCN1A sodium channel gene that result in genetic epilepsies. However, it still remains unclear how most individual mutations within SCN1A result in seizures. A previous study has shown that the K1270T (KT) mutation, linked to genetic epilepsy with febrile seizure plus (GEFS+) in humans, causes heat-induced seizure activity associated with a temperature-dependent decrease in GABAergic neuron excitability in a Drosophila knock-in model. To examine the behavioral and cellular effects of this mutation in mammals, we introduced the equivalent KT mutation into the mouse (Mus musculus) Scn1a (Scn1aKT) gene using CRISPR/Cas9 and generated mutant lines in two widely used genetic backgrounds: C57BL/6NJ and 129X1/SvJ. In both backgrounds, mice homozygous for the KT mutation had spontaneous seizures and died by postnatal day (P)23. There was no difference in mortality of heterozygous KT mice compared with wild-type littermates up to six months old. Heterozygous mutants exhibited heat-induced seizures at ∼42°C, a temperature that did not induce seizures in wild-type littermates. In acute hippocampal slices at permissive temperatures, current-clamp recordings revealed a significantly depolarized shift in action potential threshold and reduced action potential amplitude in parvalbumin (PV)-expressing inhibitory CA1 interneurons in Scn1aKT/+ mice. There was no change in the firing properties of excitatory CA1 pyramidal neurons. These results suggest that a constitutive decrease in inhibitory interneuron excitability contributes to the seizure phenotype in the mouse model.

'Resistance is futile?' - paradoxical inhibitory effects of KATP channel closure in glucagon-secreting α-cells.

By secreting insulin and glucagon, the β‐ and α‐cells of the pancreatic islets play a central role in the regulation of systemic metabolism. Both cells are equipped with ATP‐regulated potassium (KATP) channels that are regulated by the intracellular ATP/ADP ratio. In β‐cells, KATP channels are active at low (non‐insulin‐releasing) glucose concentrations. An increase in glucose leads to KATP channel closure, membrane depolarization and electrical activity that culminates in elevation of [Ca2+]i and initiation of exocytosis of the insulin‐containing secretory granules. The α‐cells are also equipped with KATP channels but they are under strong tonic inhibition at low glucose, explaining why α‐cells are electrically active under hypoglycaemic conditions and generate large Na+‐ and Ca2+‐dependent action potentials. Closure of residual KATP channel activity leads to membrane depolarization and an increase in action potential firing but this stimulation of electrical activity is associated with inhibition rather than acceleration of glucagon secretion. This paradox arises because membrane depolarization reduces the amplitude of the action potentials by voltage‐dependent inactivation of the Na+ channels involved in action potential generation. Exocytosis in α‐cells is tightly linked to the opening of voltage‐gated P/Q‐type Ca2+ channels, the activation of which is steeply voltage‐dependent. Accordingly, the inhibitory effect of the reduced action potential amplitude exceeds the stimulatory effect resulting from the increased action potential frequency. These observations highlight a previously unrecognised role of the action potential amplitude as a key regulator of pancreatic islet hormone secretion.

Abstract 477: Modeling the Effect of TBX5 Downregulation on Human Atrial Conduction Using Induced Pluripotent Stem Cell-derived Cardiomyocytes

Atrial fibrillation (AF) poses a notable healthcare burden due to a high incidence in the increasing population over age 65 and limitations of current treatment approaches. One challenge to effectively treat AF is patient-to-patient heterogeneity in the underlying mechanisms of disease. Therefore, a better understanding of AF pathogenesis and more personalized approaches to therapy could reduce risk of side effects and improve therapeutic efficacy. Genome wide association studies (GWAS) have revealed several candidate genes for AF including TBX5 , which encodes for a transcription factor involved in heart development. While work in animal models suggests that loss of TBX5 promotes atrial arrythmias, experimental evidence in human cells is lacking. We created an in vitro model of human atrial conduction using day 60+ induced pluripotent stem cell-derived atrial-like cardiomyocytes (iPSC-aCMs) differentiated from three established healthy iPSC lines. Over 90% atrial-like purity (out of 350+ alpha-actinin positive cardiomyocytes) could be achieved based on MLC2v-/MLC2a+ immunofluorescent staining. TBX5 knockdown via esiRNA resulted in downregulation of genes related to conduction velocity ( GJA5 and SCN5A ), consistent with an enhanced risk of AF. Single cell optical electrophysiology demonstrated slightly reduced action potential amplitude and upstroke velocity for TBX5 knockdown cells versus GFP esiRNA controls, suggesting a functional effect of SCN5A downregulation. Additionally, microelectrode array studies have revealed a trend towards slowed conduction velocity with TBX5 knockdown compared to GFP esiRNA controls (13.1±3.0 cm/s vs 17.0±3.8 cm/s respectively). By further investigating the functional effects of modulating transcription factors such as TBX5 in iPSC-aCMs, our results provide enhanced insight into the regulation of atrial conduction and identify potential AF-related pathways for therapeutic targeting.

Introduction of Tau Oligomers into Cortical Neurons Alters Action Potential Dynamics and Disrupts Synaptic Transmission and Plasticity.

Tau is a highly soluble microtubule-associated protein that acts within neurons to modify microtubule stability. However, abnormally phosphorylated tau dissociates from microtubules to form oligomers and fibrils which associate in the somatodendritic compartment. Although tau can form neurofibrillary tangles (NFTs), it is the soluble oligomers that appear to be the toxic species. There is, however, relatively little quantitative information on the concentration-dependent and time-dependent actions of soluble tau oligomers (oTau) on the electrophysiological and synaptic properties of neurons. Here, whole-cell patch clamp recording was used to introduce known concentrations of oligomeric full-length tau-441 into mouse hippocampal CA1 pyramidal and neocortical Layer V thick-tufted pyramidal cells. oTau increased input resistance, reduced action potential amplitude and slowed action potential rise and decay kinetics. oTau injected into presynaptic neurons induced the run-down of unitary EPSPs which was associated with increased short-term depression. In contrast, introduction of oTau into postsynaptic neurons had no effect on basal synaptic transmission, but markedly impaired the induction of long-term potentiation (LTP). Consistent with its effects on synaptic transmission and plasticity, oTau puncta could be observed in the soma, axon and in the distal dendrites of injected neurons.

Isoflurane Modulates Hippocampal Cornu Ammonis Pyramidal Neuron Excitability by Inhibition of Both Transient and Persistent Sodium Currents in Mice.

Volatile anesthetics inhibit presynaptic voltage-gated sodium channels to reduce neurotransmitter release, but their effects on excitatory neuron excitability by sodium current inhibition are unclear. The authors hypothesized that inhibition of transient and persistent neuronal sodium currents by the volatile anesthetic isoflurane contributes to reduced hippocampal pyramidal neuron excitability. Whole-cell patch-clamp recordings of sodium currents of hippocampal cornu ammonis pyramidal neurons were performed in acute mouse brain slices. The actions of isoflurane on both transient and persistent sodium currents were analyzed at clinically relevant concentrations of isoflurane. The median inhibitory concentration of isoflurane for inhibition of transient sodium currents was 1.0 ± 0.3 mM (~3.7 minimum alveolar concentration [MAC]) from a physiologic holding potential of -70 mV. Currents from a hyperpolarized holding potential of -120 mV were minimally inhibited (median inhibitory concentration = 3.6 ± 0.7 mM, ~13.3 MAC). Isoflurane (0.55 mM; ~2 MAC) shifted the voltage-dependence of steady-state inactivation by -6.5 ± 1.0 mV (n = 11, P < 0.0001), but did not affect the voltage-dependence of activation. Isoflurane increased the time constant for sodium channel recovery from 7.5 ± 0.6 to 12.7 ± 1.3 ms (n = 13, P < 0.001). Isoflurane also reduced persistent sodium current density (median inhibitory concentration = 0.4 ± 0.1 mM, ~1.5 MAC) and resurgent currents. Isoflurane (0.55 mM; ~2 MAC) reduced action potential amplitude, and hyperpolarized resting membrane potential from -54.6 ± 2.3 to -58.7 ± 2.1 mV (n = 16, P = 0.001). Isoflurane at clinically relevant concentrations inhibits both transient and persistent sodium currents in hippocampal cornu ammonis pyramidal neurons. These mechanisms may contribute to reductions in both hippocampal neuron excitability and synaptic neurotransmission.

Blockade of nifedipine‐sensitive Ca2+ channels decreases manganese accumulation on the dopamine neurons

Manganese (Mn) is an essential trace element involved in many physiological processes. Mn is transported into the cells through a number of transporters. Overexposure to Mn leads to its accumulation in the basal ganglia where it induces circuit dysregulation and a Parkinson-like syndrome referred to as manganism. The mechanisms by which Mn regulates the intrinsic firing behaviors of dopamine neurons and how Mn overexposure dysregulates this activity are not well understood. In this study, we investigated Mn's modulation of the excitability, intrinsic firing activity, Ca2+ homeostasis, and voltage-gated Ca2 channel expression in mouse dopamine neurons. We found that Mn increases the spontaneous firing activity of dopamine neuron via a concentration-dependent mechanism (10–100mM). Analysis of action potential morphology revealed that Mn truncated the amplitude and narrowed the width of action potentials and reduced coefficients of variation of the interspike interval. Unexpectedly, we found neither removal of external Ca2+ (Ca2+-free), chelation of intracellular Ca2+, nor combined chelation of internal and external Ca2+ altered Mn-regulation of action potential in dopamine neurons. Therefore, we asked whether Mn alters Ca2+ currents via the voltage-gated Ca2+ channels in the dopamine neurons. We found that Mn suppressed the peak amplitude of Ca2+ channel-mediated currents, and blockade of Ca2+ channels prevented Mn-stimulation of firing rate, reduction of action potential amplitude in dopamine neurons, and reduced 54Mn uptake in the CaV1-2, CaV1-3 expressing cells (p< 0.05, n=8–10). Finally, in vivo magnetic resonance imaging (MEMRI) revealed nifidepine-blockade of Ca2+ channels decreased Mn accumulation in the midbrain region of C57BL mice (p<0.05, n=6–8). Our data suggest a potential mechanism by which Mn can induce defects in basal ganglia function, namely a marked increase the excitability of dopaminergic neurons. Mn increases the spontaneous firing activity of dopamine neurons. Blockade of L-type Ca2+ channels inhibited Mn-stimulation of spontaneous firing activity of dopamine neurons. Manganese enhanced magnetic resonance imaging (MEMRI) provides evidence of an in vivo calcium-dependent mechanism involved in midbrain Mn accumulation. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Methylene Blue Counteracts H2S-Induced Cardiac Ion Channel Dysfunction and ATP Reduction

We have previously demonstrated that methylene blue (MB) counteracts the effects of hydrogen sulfide (H2S) cardiotoxicity by improving cardiomyocyte contractility and intracellular Ca2+ homeostasis disrupted by H2S poisoning. In vivo, MB restores cardiac contractility severely depressed by sulfide and protects against arrhythmias, ranging from bundle branch block to ventricular tachycardia or fibrillation. To dissect the cellular mechanisms by which MB reduces arrhythmogenesis and improves bioenergetics in myocytes intoxicated with H2S, we evaluated the effects of H2S on resting membrane potential (Em), action potential (AP), Na+/Ca2+ exchange current (INaCa), depolarization-activated K+ currents and ATP levels in adult mouse cardiac myocytes and determined whether MB could counteract the toxic effects of H2S on myocyte electrophysiology and ATP. Exposure to toxic concentrations of H2S (100µM) significantly depolarized Em, reduced AP amplitude, prolonged AP duration at 90% repolarization (APD90), suppressed INaCa and depolarization-activated K+ currents, and reduced ATP levels in adult mouse cardiac myocytes. Treating cardiomyocytes with MB (20µg/ml) 3min after H2S exposure restored Em, APD90, INaCa, depolarization-activated K+ currents, and ATP levels toward normal. MB improved mitochondrial membrane potential (∆ψm) and oxygen consumption rate in myocytes in which Complex I was blocked by rotenone. We conclude that MB ameliorated H2S-induced cardiomyocyte toxicity at multiple levels: (1) reversing excitation-contraction coupling defects (Ca2+ homeostasis and L-type Ca2+ channels); (2) reducing risks of arrhythmias (Em, APD, INaCa and depolarization-activated K+ currents); and (3) improving cellular bioenergetics (ATP, ∆ψm).

Ethanol Reversal of Oxycodone Tolerance in Dorsal Root Ganglia Neurons.

Oxycodone is a semisynthetic opioid compound that is widely prescribed, used, and abused today, and has a well-established role in shaping the current opioid epidemic. Previously, we have shown that tolerance develops to the antinociceptive and respiratory depressive effects of oxycodone in mice, and that a moderate dose of acute ethanol or a protein kinase C (PKC) inhibitor reversed that tolerance. To investigate further if tolerance was occurring through neuronal mechanisms, our aims for this study were to assess the effects of acute and prolonged oxycodone in isolated dorsal root ganglia (DRG) neurons and to determine if this tolerance was reversed by either ethanol or a PKC inhibitor. We found that an acute exposure to 3 μM oxycodone reduced neuronal excitability, as measured by increased threshold potentials and reduced action potential amplitude, without eliciting measurable changes in resting membrane potential. Exposure to 10 μM oxycodone for 18-24 hours prevented oxycodone's effect on neuronal excitability, indicative of tolerance development. The development of opioid tolerance was mitigated in DRG neurons from β-arrestin 2 knockout mice. Oxycodone tolerance was reversed in isolated DRG neurons by the acute application of either ethanol (20 mM) or the PKC inhibitor, bisindolylmaleimide XI hydrochloride (Bis XI), when a challenge of 3 µM oxycodone significantly reduced neuronal excitability following prolonged exposure. Through these studies, we concluded that oxycodone acutely reduced neuronal excitability, tolerance developed to this effect, and reversal of that tolerance occurred at the level of a single neuron, suggesting that reversal of oxycodone tolerance by either ethanol or Bis XI involves cellular mechanisms.

Fast Click Rate Electrocochleography and Auditory Brainstem Response in Normal-Hearing Adults Using Continuous Loop Averaging Deconvolution.

Using the continuous loop averaging deconvolution (CLAD) technique for conventional electrocochleography (ECochG) and auditory brainstem response (ABR) recordings, the effects of testing at high stimulus rates may have the potential to diagnose disorders of the inner ear and auditory nerve. First, a body of normative data using the CLAD technique must be established. Extratympanic click ECochG and ABR to seven stimulus rates using CLAD were measured simultaneously from a tympanic membrane electrode and surface electrodes on the forehead and mastoid of 42 healthy individuals. Results showed that the compound action potential (AP) of the ECochG and waves I, III, and V of the ABR decreased in amplitude and increased in latency as stimulus rate was increased from standard 7.1 clicks/s up to 507.81 clicks/s, with sharp reduction in AP amplitude at 97.66 clicks/s and reaching asymptote at 292.97 clicks/s. The summating potential (SP) of the ECochG, however, stayed relatively stable, resulting in increased SP/AP ratios with increasing rate. The SP/AP amplitude ratio showed more stability than AP amplitude findings, thus it is recommended for use in evaluation of cochlear and neural response. Results of both amplitude and latency data from this normative neural adaptation function of the auditory pathway serves as guide for improving diagnostic utility of both ECochG and ABR using CLAD as a reliable technique in distinguishing inner ear and auditory nerve disorders.

A novel points system to predict the prognosis of ulnar neuropathy at the elbow.

In this study we aimed to identify prognostic factors of ulnar neuropathy at the elbow (UNE) and developed a scoring system to establish the prognosis. We collected baseline clinical, electrophysiologic, and ultrasonographic data from 2 cohorts. The outcomes for all patients were determined on follow-up. Prognostic factors were determined using single and multiple variable analyses. A points system was developed to determine the risk for an unfavorable outcome. Of the 220 patients with UNE 178 (81%) could be re-evaluated. Four variables were retained in the prediction model for a points system. An unfavorable outcome was associated with right-sided UNE, more severe weakness of the abductor digiti minimi (ADM), and more pronounced ulnar nerve thickening. A compound muscle action potential amplitude reduction across the elbow of ≥16% (particularly if ≥ 50%) was associated with a more favorable outcome. Outcome in UNE may be predicted by scoring 4 parameters. Muscle Nerve 55: 698-705, 2017.

Effects of Deltamethrin on crayfish motor axon activity and neuromuscular transmission

Deltamethrin (DM) is a widely used pesticide known to target sodium channels. Although this compound has been studied extensively at molecular and behavioral levels, the detailed action of DM on cellular and synaptic function is less well documented. In this report, we show that DM at nanomolar concentrations can silence tonic motor output of the crayfish ventral superficial flexor (VSF) within ∼10min. Action potential (AP) amplitude was consistently reduced before silencing occurred, whereas AP duration and AP firing frequency did not change. In some synapses EPSP amplitude and synaptic delay were modified by DM, but the direction of change was not consistent. In order to better understand these diverse effects, intracellular recordings from motor axons of the crayfish opener were used for a detailed analysis. DM caused an initial, slow depolarization of resting membrane potential (Vm), which was accompanied by reduced AP amplitude but not AP duration. Resting Vm then underwent a step depolarization of ∼20mV, which we propose corresponds to the onset of the depolarization block. In addition, DM shifted the AP initiation site in some opener axons during prolonged firing. This shift occurred concomitantly with a reduction in synaptic delay. A similar reduction in synaptic delay was also detected at some VSF axons, and can be attributed to the same mechanism. Results reported here suggest that DM at low concentrations result in: (i) depolarization block of motor axons before changes in network output can be detected, (ii) variable effects on synaptic transmission, with this variability presumably due to the diverse morphology and excitability of motor axons.

Unit Activity of Hippocampal Interneurons before Spontaneous Seizures in an Animal Model of Temporal Lobe Epilepsy.

Mechanisms of seizure initiation are unclear. To evaluate the possible roles of inhibitory neurons, unit recordings were obtained in the dentate gyrus, CA3, CA1, and subiculum of epileptic pilocarpine-treated rats as they experienced spontaneous seizures. Most interneurons in the dentate gyrus, CA1, and subiculum increased their firing rate before seizures, and did so with significant consistency from seizure to seizure. Identification of CA1 interneuron subtypes based on firing characteristics during theta and sharp waves suggested that a parvalbumin-positive basket cell and putative bistratified cells, but not oriens lacunosum moleculare cells, were activated preictally. Preictal changes occurred much earlier than those described by most previous in vitro studies. Preictal activation of interneurons began earliest (>4 min before seizure onset), increased most, was most prevalent in the subiculum, and was minimal in CA3. Preictal inactivation of interneurons was most common in CA1 (27% of interneurons) and included a putative ivy cell and parvalbumin-positive basket cell. Increased or decreased preictal activity correlated with whether interneurons fired faster or slower, respectively, during theta activity. Theta waves were more likely to occur before seizure onset, and increased preictal firing of subicular interneurons correlated with theta activity. Preictal changes by other hippocampal interneurons were largely independent of theta waves. Within seconds of seizure onset, many interneurons displayed a brief pause in firing and a later, longer drop that was associated with reduced action potential amplitude. These findings suggest that many interneurons inactivate during seizures, most increase their activity preictally, but some fail to do so at the critical time before seizure onset.

Cytosolic calcium ions exert a major influence on the firing rate and maintenance of pacemaker activity in guinea-pig sinus node.

The sino-atrial node (SAN) provides the electrical stimulus to initiate every heart beat. Cellular processes underlying this activity have been debated extensively, especially with regards to the role of intracellular calcium. We have used whole-cell application of 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA), a rapid calcium chelator, to guinea pig isolated SAN myocytes to assess the effect of rapid reduction of intracellular calcium on SAN cell electrical activity. High-dose (10 mM) BAPTA induced rapid and complete cessation of rhythmic action potential (AP) firing (time to cessation 5.5 ± 1.7 s). Over a range of concentrations, BAPTA induced slowing of action potential firing and disruption of rhythmic activity, which was dose-dependent in its time of onset. Exposure to BAPTA was associated with stereotyped action potential changes similar to those previously reported in the presence of ryanodine, namely depolarization of the most negative diastolic potential, prolongation of action potentials and a reduction in action potential amplitude. These experiments are consistent with the view that cytosolic calcium is essential to the maintenance of rhythmic pacemaker activity.

Extracellular Ca2+-induced force restoration in K+-depressed skeletal muscle of the mouse involves an elevation of [K+]i: implications for fatigue.

We examined whether a Ca(2+)-K(+) interaction was a potential mechanism operating during fatigue with repeated tetani in isolated mouse muscles. Raising the extracellular Ca(2+) concentration ([Ca(2+)]o) from 1.3 to 10 mM in K(+)-depressed slow-twitch soleus and/or fast-twitch extensor digitorum longus muscles caused the following: 1) increase of intracellular K(+) activity by 20-60 mM (raised intracellular K(+) content, unchanged intracellular fluid volume), so that the K(+)-equilibrium potential increased by ∼10 mV and resting membrane potential repolarized by 5-10 mV; 2) large restoration of action potential amplitude (16-54 mV); 3) considerable recovery of excitable fibers (∼50% total); and 4) restoration of peak force with the peak tetanic force-extracellular K(+) concentration ([K(+)]o) relationship shifting rightward toward higher [K(+)]o. Double-sigmoid curve-fitting to fatigue profiles (125 Hz for 500 ms, every second for 100 s) showed that prior exposure to raised [K(+)]o (7 mM) increased, whereas lowered [K(+)]o (2 mM) decreased, the rate and extent of force loss during the late phase of fatigue (second sigmoid) in soleus, hence implying a K(+) dependence for late fatigue. Prior exposure to 10 mM [Ca(2+)]o slowed late fatigue in both muscle types, but was without effect on the extent of fatigue. These combined findings support our notion that a Ca(2+)-K(+) interaction is plausible during severe fatigue in both muscle types. We speculate that a diminished transsarcolemmal K(+) gradient and lowered [Ca(2+)]o contribute to late fatigue through reduced action potential amplitude and excitability. The raised [Ca(2+)]o-induced slowing of fatigue is likely to be mediated by a higher intracellular K(+) activity, which prolongs the time before stimulation-induced K(+) efflux depolarizes the sarcolemma sufficiently to interfere with action potentials.

Lambert-Eaton myasthenic syndrome in patients with small cell lung cancer: Report of five cases

To further evaluate the clinical characteristics of small cell lung cancer (SCLC) with Lambert-Eaton syndrome. We reviewed the patient database of our hospital from 2001 to 2013 to evaluate and analyze the patients of SCLC with Lambert-Eaton syndrome. The clinical characteristics and prognosis of the patients were analyzed in this retrospective study. From reviewing our hospital database, we included 5 SCLC patients with Lambert-Eaton syndrome from 202 SCLC subjects with an incidence rate of 2.5%. The median age of the 5 patients was 52 (41-71) with 4 male and 1 female. The myasthenia symptom can be detected in 2-20 months before the pathology confirmation for small cell lung carcinoma. The general electromyography characteristics of Lambert-Eaton syndrome was reduction in action potential amplitude after repetitive peripheral never stimulation at low frequency and increased amplitude at high frequency. Lambert-Eaton syndrome was sometimes found in patients with SCLC which was useful for diagnosis of non-small cell lung carcinoma in a relatively early stage.