Transient Sodium Research Articles

6619 An Unlikely Cause of Oligomenorrhea: Acromegaly Secondary to a Sparsely Granulated, Somatotroph-Lactotroph Adenoma

Abstract Disclosure: S.I. Alicea: None. Y. Wu: None. J. Marquez: None. C.S. Botero Suarez: None. M. Kinaan: None. Introduction: Acromegaly most commonly presents as a pituitary tumor that causes excessive production ofgrowth hormone (GH); and rarely due to excess of GHRH or ectopic production of GH. Approximately 15% of surgically removed pituitary adenomas represent GH-producing neoplasms, and about 5% are bihormonal, secreting both GH and prolactin (PRL). We present a case of an unexpected presentation of oligomenorrhea which ended up with the diagnosis of acromegaly secondary to plurihormonal mixed somatotroph-lactotroph sparsely granulated adenoma. Case Description A 32-year-old female with history of prediabetes was referred to our clinic by her gynecologistfor evaluation of oligomenorrhea which was initially attributed to polycystic ovarian syndrome.She reported menarche at age 10 and has experienced irregular menses and periods of amenorrhea over the years. Physical exam revealed macroglossia, a widened thickened nose, acanthosis nigricans in the neck skin folds, facial hair thickening, and significant thickening of all fingers, toes and soft tissues. Given physical exam findings, we evaluated the patient for acromegaly and lab testing revealed markedly high IGF I, mildly elevated prolactin, and hemoglobin A1C of 5.7%. An MRI of the brain with IV contrast revealed a heterogeneously enhancing pituitary macroadenoma measuring 2.9 x 2.9 x 2.2 cm with suprasellar extension resulting in mass effect on the optic chiasm without definite cavernous sinus extension. She was started on Cabergoline 0.5mg twice weekly temporarily and underwent pituitary transsphenoidal resection. Pathology results revealed tumor cells that were positive for Chromogranin and Cam5.2. About 10% of cells showed immunoreactivity for Prolactin and negative for TSH, ACTH, FSH, LH and immunostains. There was also weak focal (about 2%) immunoreactivity for GH. Occasional mitotic figures were present. The MIB-1 proliferation index was 3%. The reticulin stain demonstrates loss of acinar architecture, supporting the diagnosis. Aside from transient sodium fluctuations consistent with triphasic response, she had no long-lasting postoperative complications. One month after her surgery, her IGF I level and hemoglobin A1C are trending down and she reports symptomatic relief. She continues follow up in our clinic. Discussion This patient has acromegaly secondary to a mixed somatotroph-lactotroph sparsely granulated adenoma. Sparsely granulated adenomas are more common in younger populations, can be more aggressive, and are less responsive to somatostatin analogs. Early detection and treatment is imperative in the prevention of complications secondary to the disease. Our case will closely examine the differences in the clinical, prognostic, and pathologic features of sparsely- vs. densely granulated adenomas. We will also discuss the effects of acromegaly on gonadal function. Presentation: 6/1/2024

Redshifted Sodium Transient near Exoplanet Transit

Neutral sodium (Na i) is an alkali metal with a favorable absorption cross section such that tenuous gases are easily illuminated at select transiting exoplanet systems. We examine both the time-averaged and time-series alkali spectral flux individually, over 4 nights at a hot Saturn system on a ∼2.8 day orbit about a Sun-like star WASP-49 A. Very Large Telescope/ESPRESSO observations are analyzed, providing new constraints. We recover the previously confirmed residual sodium flux uniquely when averaged, whereas night-to-night Na i varies by more than an order of magnitude. On HARPS/3.6 m Epoch II, we report a Doppler redshift at v Γ,NaD = + 9.7 ± 1.6 km s−1 with respect to the planet’s rest frame. Upon examining the lightcurves, we confirm night-to-night variability, on the order of ∼1%–4% in NaD, rarely coinciding with exoplanet transit, not readily explained by stellar activity, starspots, tellurics, or the interstellar medium. Coincident with the ∼+10 km s−1 Doppler redshift, we detect a transient sodium absorption event dF NaD/F ⋆ = 3.6% ± 1% at a relative difference of ΔF NaD(t) ∼ 4.4% ± 1%, lasting Δt NaD ≳ 40 minutes. Since exoplanetary alkali signatures are blueshifted due to the natural vector of radiation pressure, estimated here at roughly ∼−5.7 km s−1, the radial velocity is rather at +15.4 km s−1, far larger than any known exoplanet system. Given that the redshift magnitude v Γ is in between the Roche limit and dynamically stable satellite orbits, the transient sodium may be a putative indication of a natural satellite orbiting WASP-49 A b.

CESAR experiment: Sodium boiling during Transient OverPower

In the framework of nuclear revival under the constraint of global warming and in the context of the emergence of new small modular reactor concepts, sodium cooled fast breeders seem to be a good candidate for maximizing the energy yield of the fuel and burning actinides. In the case of rapid reactivity insertion, characterizing transient sodium boiling is essential, as it can lead to dry out and rupture of fuel pins, but also as it has an impact on core reactivity. As sodium is a metal with a low Prandtl number, its boiling behavior is different from that of water. In order to provide insights and data on boiling of sodium during transient overpower, past experimental results obtained in the frame of the CESAR program (Caracterisation de l’Ebullition du Sodium en Accident de Réactivité) performed at CEA Grenoble in the 70th are described and main learnings are given. The CESAR test loop and experimental procedure are described, and results of seven transient tests with different inlet flow rates, temperatures, pressures and transient powers are described and interpreted on the basis of a comparison with single-phase simulations. The phenomenon of sodium superheat at boiling onset is studied. These data, which are rare in the literature, can be used to validate simulation tools.

Estimation of persistent sodium-current density in rat hippocampal mossy fibre boutons: Correction of space-clamp errors.

We used whole-cell patch clamp to estimate the stationary voltage dependence of persistent sodium-current density (iNaP) in rat hippocampal mossy fibre boutons. Cox's method for correcting space-clamp errors was extended to the case of an isopotential compartment with attached neurites. The method was applied to voltage-ramp experiments, in which iNaP is assumed to gate instantaneously. The raw estimates of iNaP led to predicted clamp currents that were at variance with observation, hence an algorithm was devised to improve these estimates. Optionally, the method also allows an estimate of the membrane specific capacitance, although values of the axial resistivity and seal resistance must be provided. Assuming that membrane specific capacitance and axial resistivity were constant, we conclude that seal resistance continued to fall after adding TTX to the bath. This might have been attributable to a further deterioration of the seal after baseline rather than an unlikely effect of TTX. There was an increase in the membrane specific resistance in TTX. The reason for this is unknown, but it meant that iNaP could not be determined by simple subtraction. Attempts to account for iNaP with a Hodgkin-Huxley model of the transient sodium conductance met with mixed results. One thing to emerge was the importance of voltage shifts. Also, a large variability in previously reported values of transient sodium conductance in mossy fibre boutons made comparisons with our results difficult. Various other possible sources of error are discussed. Simulations suggest a role for iNaP in modulating the axonal attenuation of EPSPs. KEY POINTS: We used whole-cell patch clamp to estimate the stationary voltage dependence of persistent sodium-current density (iNaP) in rat hippocampal mossy fibre boutons, using a KCl-based internal (pipette) solution and correcting for the liquid junction potential (2mV). Space-clamp errors and deterioration of the patch-clamp seal during the experiment were corrected for by compartmental modelling. Attempts to account for iNaP in terms of the transient sodium conductance met with mixed results. One possibility is that the transient sodium conductance is higher in mossy fibre boutons than in the axon shaft. The analysis illustrates the need to account for various voltage shifts (Donnan potentials, liquid junction potentials and, possibly, other voltage shifts). Simulations suggest a role for iNaP in modulating the axonal attenuation of excitatory postsynaptic potentials, hence analog signalling by dentate granule cells.

Inferring Parameters of Pyramidal Neuron Excitability in Mouse Models of Alzheimer’s Disease Using Biophysical Modeling and Deep Learning

Alzheimer’s disease (AD) is believed to occur when abnormal amounts of the proteins amyloid beta and tau aggregate in the brain, resulting in a progressive loss of neuronal function. Hippocampal neurons in transgenic mice with amyloidopathy or tauopathy exhibit altered intrinsic excitability properties. We used deep hybrid modeling (DeepHM), a recently developed parameter inference technique that combines deep learning with biophysical modeling, to map experimental data recorded from hippocampal CA1 neurons in transgenic AD mice and age-matched wildtype littermate controls to the parameter space of a conductance-based CA1 model. Although mechanistic modeling and machine learning methods are by themselves powerful tools for approximating biological systems and making accurate predictions from data, when used in isolation these approaches suffer from distinct shortcomings: model and parameter uncertainty limit mechanistic modeling, whereas machine learning methods disregard the underlying biophysical mechanisms. DeepHM addresses these shortcomings by using conditional generative adversarial networks to provide an inverse mapping of data to mechanistic models that identifies the distributions of mechanistic modeling parameters coherent to the data. Here, we demonstrated that DeepHM accurately infers parameter distributions of the conductance-based model on several test cases using synthetic data generated with complex underlying parameter structures. We then used DeepHM to estimate parameter distributions corresponding to the experimental data and infer which ion channels are altered in the Alzheimer’s mouse models compared to their wildtype controls at 12 and 24 months. We found that the conductances most disrupted by tauopathy, amyloidopathy, and aging are delayed rectifier potassium, transient sodium, and hyperpolarization-activated potassium, respectively.

Coupling of Slack and NaV1.6 sensitizes Slack to quinidine blockade and guides anti-seizure strategy development.

Quinidine has been used as an anticonvulsant to treat patients with KCNT1-related epilepsy by targeting gain-of-function KCNT1 pathogenic mutant variants. However, the detailed mechanism underlying quinidine's blockade against KCNT1 (Slack) remains elusive. Here, we report a functional and physical coupling of the voltage-gated sodium channel NaV1.6 and Slack. NaV1.6 binds to and highly sensitizes Slack to quinidine blockade. Homozygous knockout of NaV1.6 reduces the sensitivity of native sodium-activated potassium currents to quinidine blockade. NaV1.6-mediated sensitization requires the involvement of NaV1.6's N- and C-termini binding to Slack's C-terminus and is enhanced by transient sodium influx through NaV1.6. Moreover, disrupting the Slack-NaV1.6 interaction by viral expression of Slack's C-terminus can protect against SlackG269S-induced seizures in mice. These insights about a Slack-NaV1.6 complex challenge the traditional view of 'Slack as an isolated target' for anti-epileptic drug discovery efforts and can guide the development of innovative therapeutic strategies for KCNT1-related epilepsy.

Bupleurum exerts antiarrhythmic effects by inhibiting L-type calcium channels in mouse ventricular myocytes

BackgroundBupleurum (Bup), is a traditional effective medicine to treat colds and fevers in clinics. Multiple studies have demonstrated that Bup exhibites various biological activities, including cardioprotective effects, anti-inflammatory, anticancer, antipyretic, antimicrobial, and antiviral effects, etc. Currently, the effects of Bup on cardiac electrophysiology have not been reported yet. MethodsElectrocardiogram recordings were used to investigate the effects of Bup on aconitine-induced arrhythmias. Patch-clamp techniques were used to explore the effects of Bup on APs and ion currents. ResultsBup reduced the incidence of ventricular fibrillation (VF) and delayed the onset time of ventricular tachycardia (VT) in mice. Additionally, Bup (40 mg/mL) suppressed DADs induced by high-Ca2+ and shortened action potential duration at 50 % completion of repolarization (APD50) and action potential duration at 90 % completion of repolarization (APD90) to 60.89 % ± 8.40 % and 68.94 % ± 3.24 % of the control, respectively. Moreover, Bup inhibited L-type calcium currents (ICa.L) in a dose-dependent manner, with an IC50 value of 25.36 mg/mL. Furthermore, Bup affected the gated kinetics of L-type calcium channels by slowing down steady-state activation, accelerating the steady-state inactivation, and delaying the inactivation-recovery process. However, Bup had no effects on the Transient sodium current (INa.T), ATX II-increased late sodium current (INa.L), transient outward current (Ito), delayed rectifier potassium current (IK), or inward rectifier potassium current (IK1). ConclusionBup is an antiarrhythmic agent that may exert its antiarrhythmic effects by inhibiting L-type calcium channels.

Dynamic Analysis of Neuron Models

Based on the Hodgkin–Huxley theory, this paper establishes several nonlinear system models, analyzes the models’ stability, and studies the conditions for repetitive discharge of neuronal membrane potential. Our dynamic analysis showed that the main channel currents (the fast transient sodium current, the potassium delayed rectifier current, and the fixed leak current) of a neuron determine its dynamic properties and that the GHK formula will greatly widen the stimulation current range of the repetitive discharge condition compared with the Nernst equation. The model including the change in ion concentration will lead to spreading depression (SD)-like depolarization, and the inclusion of a Na-K pump will weaken the current stimulation effect by decreasing the extracellular K accumulation. The results indicate that the Hodgkin–Huxley model is suitable for describing the response to initial stimuli, but due to changes in ion concentration, it is not suitable for describing the response to long-term stimuli.

Numerical studies on liquid sodium flow boiling in a 7-pin hexagonal subassembly towards flow rundown scenario in SFR

The present study is intended for the development of high resolution CFD based model for the prediction of two-phase flow and heat transfer characteristics of liquid sodium in a 7-pin bundle. The sodium flow boiling from its inception to nucleate boiling and the forced convective vaporization regimes are analyzed by developing an Eulerian-Eulerian model (two-fluid model) using flow regime dependent constitutive correlations and modified non-equilibrium wall boiling model. The Algebraic Interfacial Area Density (AIAD) model is implemented for providing required closure terms as flow regime dependent based on the local flow topology within the two-fluid model. The sodium flow boiling simulations are performed in a 7-pin subassembly using the model under constant wall heat flux for different inlet mass flow rates and predicted the quasi-steady boiling. The radial and axial void fraction progress in the flow sub-channels, variation of sodium temperature, and wall boiling components along the heated pin length are numerically predicted. Also analyzed the transient sodium boiling under flow rundown scenario in the 7-pin subassembly with a continuous reduction in the inlet mass flow rate under constant wall heat flux. The prediction of wall temperature variation during this flow scenario confirmed the incidence of local dry-out at the end of the transient which causes loss of heat transfer from the pin surface. Also, the mechanistic model based evaluations for wall heat transfer coefficient and possible flow regimes are obtained based on the flow and thermal conditions predicted.

Low-dimensional models of single neurons: a review.

The classical Hodgkin-Huxley (HH) point-neuron model of action potential generation is four-dimensional. It consists of four ordinary differential equations describing the dynamics of the membrane potential and three gating variables associated to a transient sodium and a delayed-rectifier potassium ionic currents. Conductance-based models of HH type are higher-dimensional extensions of the classical HH model. They include a number of supplementary state variables associated with other ionic current types, and are able to describe additional phenomena such as subthreshold oscillations, mixed-mode oscillations (subthreshold oscillations interspersed with spikes), clustering and bursting. In this manuscript we discuss biophysically plausible and phenomenological reduced models that preserve the biophysical and/or dynamic description of models of HH type and the ability to produce complex phenomena, but the number of effective dimensions (state variables) is lower. We describe several representative models. We also describe systematic and heuristic methods of deriving reduced models from models of HH type.

Scalable, Green Synthesis of Heteroaromatic Amine-boranes

In situ generated, transient sodium monohydroxyborohydride readily reacts with a present amine to form amine-borane adducts in ethyl acetate at room temperature. Synthesis of heteroaromatic pyridine-, 2-picoline-, and 5-ethyl-2-methylpyridine-boranes, those relevant to large-scale reductive aminations, has been demonstrated at 100 mmol scale, and pyridine-borane at 1.1 mole scale. This first report substituting ethyl acetate for tetrahydrofuran, the traditional solvent for amine-borane synthesis, allows for activation of sodium borohydride by the aqueous portion of the heterogeneous dual-solvent system. These factors make this green protocol more economical than those currently available for the large-scale production of amine-boranes as demonstrated, quantitatively, by the computed green chemistry metrics.

The effects of membrane potential oscillations on the excitability of rat hypoglossal motoneurons.

Oscillations in membrane potential induced by synaptic inputs and intrinsic ion channel activity play a role in regulating neuronal excitability, but the precise mechanisms underlying their contributions remain largely unknown. Here we used electrophysiological and modeling approaches to investigate the effects of Gaussian white noise injected currents on the membrane properties and discharge characteristics of hypoglossal (HG) motoneurons in P16-21 day old rats. We found that the noise-induced membrane potential oscillations facilitated spike initiation by hyperpolarizing the cells’ voltage threshold by 3.1 ± 1.0 mV and reducing the recruitment current for the tonic discharges by 0.26 ± 0.1 nA, on average (n = 59). Further analysis revealed that the noise reduced both recruitment and decruitment currents by 0.26 ± 0.13 and 0.33 ± 0.1 nA, respectively, and prolonged the repetitive firing. The noise also increased the slopes of frequency-current (F-I) relationships by 1.1 ± 0.2 Hz/nA. To investigate the potential mechanisms underlying these findings, we constructed a series of HG motoneuron models based on their electrophysiological properties. The models consisted of five compartments endowed with transient sodium (NaT), delayed-rectify potassium [K(DR)], persistent sodium (NaP), calcium-activated potassium [K(AHP)], L-type calcium (CaL) and H-current channels. In general, all our experimental results could be well fitted by the models, however, a modification of standard Hodgkin-Huxley kinetics was required to reproduce the changes in the F-I relationships and the prolonged discharge firing. This modification, corresponding to the noise generated by the stochastic flicker of voltage-gated ion channels (channel flicker, CF), was an adjustable sinusoidal function added to kinetics of the channels that increased their sensitivity to subthreshold membrane potential oscillations. Models with CF added to NaP and CaL channels mimicked the noise-induced alterations of membrane properties, whereas models with CF added to NaT and K(DR) were particularly effective in reproducing the noise-induced changes for repetitive firing observed in the real motoneurons. Further analysis indicated that the modified channel kinetics enhanced NaP- and CaL-mediated inward currents thus increasing the excitability and output of HG motoneurons, whereas they produced relatively small changes in NaT and K(DR), thus balancing these two currents and triggering variability of repetitive firing. This study provided insight into the types of membrane channel mechanisms that might underlie oscillation-induced alterations of neuronal excitability and motor output in rat HG motoneurons.

Coexistence of Charcot-Marie-Tooth 1A and nondystrophic myotonia due to PMP22 duplication and SCN4A pathogenic variants: a case report

BackgroundCharcot-Marie-Tooth disease (CMT) is a genetically heterogeneous hereditary neuropathy, and CMT1A is the most common form; it is caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. Mutations in the transient sodium channel Nav1.4 alpha subunit (SCN4A) gene underlie a diverse group of dominantly inherited nondystrophic myotonias that run the spectrum from subclinical myopathy to severe muscle stiffness, disabling weakness, or frank episodes of paralysis.Case presentationWe describe a Chinese family affected by both CMT1A and myotonia with concomitant alterations in both the PMP22 and SCN4A genes. In this family, the affected proband inherited the disease from his father in an autosomal dominant manner. Genetic analysis confirmed duplication of the PMP22 gene and a missense c.3917G > C (p. Gly1306Ala) mutation in SCN4A in both the proband and his father. The clinical phenotype in the proband showed the combined involvement of skeletal muscle and peripheral nerves. Electromyography showed myopathic changes, including myotonic discharges. MRI revealed the concurrence of neurogenic and myogenic changes in the lower leg muscles. Sural nerve biopsies revealed a chronic demyelinating and remyelinating process with onion bulb formations in the proband. The proband’s father presented with confirmed subclinical myopathy, very mild distal atrophy and proximal hypertrophy of the lower leg muscles, pes cavus, and areflexia.ConclusionThis study reports the coexistence of PMP22 duplication and SCN4A mutation. The presenting features in this family suggested that both neuropathy and myopathy were inherited in an autosomal dominant manner. The proband had a typical phenotype of sodium channel myotonia (SCM) and CMT1A. However, his father with the same mutations presented a much milder clinical phenotype. Our study might expand the genetic and phenotypic spectra of neuromuscular disorders with concomitant mutations.

Dopaminergic Inhibition of Na+ Currents in Vestibular Inner Ear Afferents

Inner ear hair cells form synapses with afferent terminals and afferent neurons carry signals as action potentials to the central nervous system. Efferent neurons have their origins in the brainstem and some make synaptic contact with afferent dendrites beneath hair cells. Several neurotransmitters have been identified that may be released from efferent terminals to modulate afferent activity. Dopamine is a candidate efferent neurotransmitter in both the vestibular and auditory systems. Within the cochlea, activation of dopamine receptors may reduce excitotoxicity at the inner hair cell synapse via a direct effect of dopamine on afferent terminals. Here we investigated the effect of dopamine on sodium currents in acutely dissociated vestibular afferent calyces to determine if dopaminergic signaling could also modulate vestibular responses. Calyx terminals were isolated along with their accompanying type I hair cells from the cristae of gerbils (P15-33) and whole cell patch clamp recordings performed. Large transient sodium currents were present in all isolated calyces; compared to data from crista slices, resurgent Na+ currents were rare. Perfusion of dopamine (100 μM) in the extracellular solution significantly reduced peak transient Na+ currents by approximately 20% of control. A decrease in Na+ current amplitude was also seen with extracellular application of the D2 dopamine receptor agonist quinpirole, whereas the D2 receptor antagonist eticlopride largely abolished the response to dopamine. Inclusion of the phosphatase inhibitor okadaic acid in the patch electrode solution occluded the response to dopamine. The reduction in calyx sodium current in response to dopamine suggests efferent signaling through D2 dopaminergic receptors may occur via common mechanisms to decrease excitability in inner ear afferents.

Activation of the intestinal tissue renin-angiotensin system by transient sodium loading in salt-sensitive rats.

Background:The renal tissue renin-angiotensin system is known to be activated by salt loading in salt-sensitive rats; however, the response in other organs remains unclear.Method:Spontaneously hypertensive rats were subjected to normal tap water or transient high-salt-concentration water from 6 to 14 weeks of age and were thereafter given normal tap water. From 18 to 20 weeks of age, rats given water with a high salt concentration were treated with an angiotensin II type 1 receptor blocker, valsartan.Results:Sustained blood pressure elevation by transient salt loading coincided with a persistent decrease in the fecal sodium content and sustained excess of the circulating volume in spontaneously hypertensive rats. Administration of valsartan sustainably reduced the blood pressure and normalized the fecal sodium levels. Notably, transient salt loading persistently induced the intestinal tissue renin-angiotensin system and enhanced sodium transporter expression exclusively in the small intestine of salt-sensitive rats, suggesting the potential connection of intestinal sodium absorption to salt sensitivity.Conclusion:These results reveal the previously unappreciated contribution of the intestinal tissue renin-angiotensin system to sodium homeostasis and blood pressure regulation in the pathophysiology of salt-sensitive hypertension.

WS4.3. Overview of Axonal Excitability Studies

Nerve excitability testing is a non-invasive neurophysiological technique, which investigates nerve functions in vivo . While nerve conduction studies deliver supramaximal stimuli to measure conduction velocities and the number of large myelinated fibres, nerve excitability studies use weaker stimuli and measure strength of stimuli, which evoke target compound muscle action potential or sensory nerve action potential amplitudes. The combination of conditioning and test stimuli, with various strength and duration, can examine functions of various types of ion channels and ion pumps and exchangers, which are located in peripheral nerve axons, and membrane potential. Several paradigms, such as strength-duration properties, threshold electrotonus, current-threshold relationship and recovery cycle, are assessed in this testing, and alterations of parameters in these paradigms indicate changes in those functions. This technique has disclosed various pathophysiological alterations mainly in genetic and acquired channelopathies. A famous study, using this technique, disclosed an effect of puffer fish poisoning for nerve excitability. Tetrodotoxin is known to block sodium channels, and salient reductions of strength-duration time constant and refractoriness in recovery cycle, makers of persistent and transient sodium channel functions, respectively, were disclosed in patients with tetrodotoxin intoxation. This study firstly visualized an effect of tetrodotoxin for the human peripheral nerve. In another study, increased strength-duration time constant, i.e. increased excitability, was revealed in patients with neuropathic pain and muscle cramps. Mexiletine treatment, a sodium channel blocker, for these patients relieved those symptoms and decreased strength-duration time constant. As those studies, recent studies, using this testing, have disclosed an impact of altered ion channel functions for neurological diseases and utility of this technique as a treatment biomarker. In this session, I plan to introduce the principle of this testing and recent advances in clarification of pathophysiology in neurological diseases and treatment developments, using this testing.

Inhibition of IL-1β Secretion and Mitochondria Respiration by Arsenite which acts on Myocardial Ischemia-Reperfusion Injury

Arsenite (NaAsO2) is a potent toxin that significantly contributes to human pathogenesis. Chronic exposure to arsenite results in various diseases. The physiologically important biological target(s) of arsenite exposure is largely unknown. Here we found that transient sodium arsenite treatment (1) blocks nigericin or Rotenone induced IL- 1β secretion; (2) inhibits mitochondrial respiration with complex I-linked substrate; (3) induces Heme oxygenase-1 (HO-1) in myocardial tissue, (4) attenuates the myocardial ischemia-reperfusion injury in an in vivo model of rats. The causal relationship among these activities needs further investigation.

Sodium-Calcium Exchanger Reverse Mode Sustains Dichotomous Ion Fluxes Required for Procoagulant COAT Platelet Formation.

Procoagulant collagen-and-thrombin (COAT)-activated platelets represent a subpopulation of activated platelets, which retain a coat of prohemostatic proteins and express phosphatidylserine on their surface. Dichotomous intracellular signaling generating procoagulant platelet activity instead of traditional aggregating endpoints is still not fully elucidated. It has been demonstrated that secondary messengers such as calcium and sodium play a critical role in platelet activation. Therefore, we developed a flow cytometric analysis to investigate intracellular ion fluxes simultaneously during generation of aggregating and procoagulant platelets. Human platelets were activated by convulxin-plus-thrombin. Cytosolic calcium, sodium, and potassium ion fluxes were visualized by specific ion probes and analyzed by flow cytometry. We observed high and prolonged intracellular calcium concentration, transient sodium increase, and fast potassium efflux in COAT platelets, whereas aggregating non-COAT platelets rapidly decreased their calcium content, maintaining higher cytosolic sodium, and experiencing lower and slower potassium depletion. Considering these antithetical patterns, we investigated the role of the sodium-calcium exchanger (NCX) during convulxin-plus-thrombin activation. NCX inhibitors, CBDMB and ORM-10103, dose-dependently reduced the global calcium mobilization induced by convulxin-plus-thrombin activation and dose-dependently prevented formation of procoagulant COAT platelets. Our data demonstrate that both NCX modes are used after convulxin-plus-thrombin-induced platelet activation. Non-COAT platelets use forward-mode NCX, thus pumping calcium out and moving sodium in, while COAT platelets rely on reverse NCX function, which pumps additional calcium into the cytosol, by extruding sodium. In conclusion, we described for the first time the critical and dichotomous role of NCX function during convulxin-plus-thrombin-induced platelet activation.

Alterations in Intrinsic and Synaptic Properties of Hippocampal CA1 VIP Interneurons During Aging.

Learning and memory deficits are hallmarks of the aging brain, with cortical neuronal circuits representing the main target in cognitive deterioration. While GABAergic inhibitory and disinhibitory circuits are critical in supporting cognitive processes, their roles in age-related cognitive decline remain largely unknown. Here, we examined the morphological and physiological properties of the hippocampal CA1 vasoactive intestinal peptide/calretinin-expressing (VIP+/CR+) type 3 interneuron-specific (I-S3) cells across mouse lifespan. Our data showed that while the number and morphological features of I-S3 cells remained unchanged, their firing and synaptic properties were significantly altered in old animals. In particular, the action potential duration and the level of steady-state depolarization were significantly increased in old animals in parallel with a significant decrease in the maximal firing frequency. Reducing the fast-delayed rectifier potassium or transient sodium conductances in I-S3 cell computational models could reproduce the age-related changes in I-S3 cell firing properties. However, experimental data revealed no difference in the activation properties of the Kv3.1 and A-type potassium currents, indicating that transient sodium together with other ion conductances may be responsible for the observed phenomena. Furthermore, I-S3 cells in aged mice received a stronger inhibitory drive due to concomitant increase in the amplitude and frequency of spontaneous inhibitory currents. These age-associated changes in the I-S3 cell properties occurred in parallel with an increased inhibition of their target interneurons and were associated with spatial memory deficits and increased anxiety. Taken together, these data indicate that VIP+/CR+ interneurons responsible for local circuit disinhibition survive during aging but exhibit significantly altered physiological properties, which may result in the increased inhibition of hippocampal interneurons and distorted mnemonic functions.

A modeling study of spinal motoneuron recruitment regulated by ionic channels during fictive locomotion.

During fictive locomotion cat lumbar motoneurons exhibit changes in membrane proprieties including a decrease in voltage threshold (Vth), afterhyperpolarization (AHP) and input resistance (Rin) and an increase in non-linear membrane property. The impact of these changes on the motoneuron recruitment remains unknown. Using modeling approach we investigated the channel mechanism regulating the motoneuron recruitment. Three types of motoneuron pools including slow (S), fatigue-resistant (FR) and fast-fatigable (FF) motoneurons were constructed based on the membrane proprieties of cat lumbar motoneurons. The transient sodium (NaT), persistent sodium (NaP), delayed-rectifier potassium [K(DR)], Ca2+-dependent K+ [K(AHP)] and L-type calcium (CaL) channels were included in the models. Simulation results showed that (1) Strengthening synaptic inputs increased the number of recruitments in all three types of motoneurons following the size principle. (2) Increasing NaT or NaP or decreasing K(DR) or K(AHP) lowered rheobase of spike generation thus increased recruitment of motoneuron pools. (3) Decreasing Rin reduced recruitment in all three types of motoneurons. (4) The FF-type motoneuron pool, followed by FR- and S-type, were the most sensitive to increase of synaptic inputs, reduction of Rin, upregulation of NaT and NaP, and downregulation of K(DR) and K(AHP). (5) Increasing CaL enhanced overall discharge rate of motoneuron pools with little effect on the recruitment. Simulation results suggested that modulation of ionic channels altered the output of motoneuron pools with either modulating the number of recruited motoneurons or regulating the overall discharge rate of motoneuron pools. Multiple channels contributed to the recruitment of motoneurons with interaction of excitatory and inhibitory synaptic inputs during walking.