GPD1L-A306del modifies sodium current in a family carrying the dysfunctional SCN5A-G1661R mutation associated with Brugada syndrome.

Loss-of-function variants of SCN5A, encoding the sodium channel alpha subunit Nav1.5 are associated with high phenotypic variability and multiple cardiac presentations, while underlying mechanisms are incompletely understood. Here we investigated a family with individuals affected by Brugada Syndrome (BrS) of different severity and aimed to unravel the underlying genetic and electrophysiological basis.

Glutamate transporter contribution to retinal ganglion cell vulnerability in a rat model of multiple sclerosis.

Glial glutamate transporters actively participate in neurotransmission and have a fundamental role in determining the ambient glutamate concentration in the extracellular space. Their expression is dynamically regulated in many diseases, including experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. In EAE, a downregulation has been reported which may render neurons more susceptible to glutamate excitotoxicity.

Histone deacetylase 2-dependent ventricular electrical remodeling in a porcine model of early heart failure.

Aims: Heart failure (HF) is linked to electrical remodeling that promotes ventricular arrhythmias. Underlying molecular signaling is insufficiently understood, in particular concerning patients with early disease stages. Previous observations suggest a key role for epigenetic mechanisms in cardiac remodeling processes.

The COVID-19 Army Rapid Assessment Tool (CARAT) for Management of COVID-19 in the Deployed Setting.

The COVID-19 pandemic poses unique challenges within the austere clinical setting, and the time between patient presentation and deterioration is a critical opportunity for intervention. In some cases, this may be a life-saving transfer to a higher level of care. US Central Command (CENTCOM) has provided valuable guidance for COVID-19 management in the operational environment,1 and has proposed the National Early Warning System 2 (NEWS2) scoring tool as a useful adjunct to gauging illness severity.

Epigenetic regulation of cardiac electrophysiology in atrial fibrillation: HDAC2 determines action potential duration and suppresses NRSF in cardiomyocytes.

Atrial fibrillation (AF) is associated with electrical remodeling, leading to cellular electrophysiological dysfunction and arrhythmia perpetuation. Emerging evidence suggests a key role for epigenetic mechanisms in the regulation of ion channel expression. Histone deacetylases (HDACs) control gene expression through deacetylation of histone proteins.

The C-terminal HCN4 variant P883R alters channel properties and acts as genetic modifier of atrial fibrillation and structural heart disease.

Atrial fibrillation (AF) is the most frequent sustained arrhythmia and can lead to structural cardiac changes, known as tachycardia-induced cardiomyopathy (TIC). HCN4 is implicated in spontaneous excitation of the sinoatrial node, while channel dysfunction has been associated with sinus bradycardia, AF and structural heart disease. We here asked whether HCN4 mutations may contribute to the development of TIC, as well.

Augmentation of myocardial I dysregulates calcium homeostasis and causes adverse cardiac remodeling.

HCN channels underlie the depolarizing funny current (I) that contributes importantly to cardiac pacemaking. I is upregulated in failing and infarcted hearts, but its implication in disease mechanisms remained unresolved. We generated transgenic mice (HCN4) to assess functional consequences of HCN4 overexpression-mediated I increase in cardiomyocytes to levels observed in human heart failure.

Pacemaker cell characteristics of differentiated and HCN4-transduced human mesenchymal stem cells.

Aims: Cell-based biological pacemakers aim to overcome limitations and side effects of electronic pacemaker devices. We here developed and tested different approaches to achieve nodal-type differentiation using human adipose- and bone marrow-derived mesenchymal stem cells (haMSC, hbMSC).

Main Methods: haMSC and hbMSC were differentiated using customized protocols.

Selective Vulnerability of αOFF Retinal Ganglion Cells during Onset of Autoimmune Optic Neuritis.

Retinal ganglion cells (RGCs), a diverse body of neurons which relay visual signals from the retina to the higher processing regions of the brain, are susceptible to neurodegenerative processes in several diseases affecting the retina. Previous evidence shows that RGCs are damaged at early stages of autoimmune optic neuritis (AON), prior to subsequent degeneration of the optic nerve. In order to study cell type-specific vulnerability of RGCs we performed immunohistochemical and patch-clamp electrophysiological analyses of RGCs following induction of AON using the experimental autoimmune encephalomyelitis model in Brown Norway rats.

TREK-1 (K2.1) K channels are suppressed in patients with atrial fibrillation and heart failure and provide therapeutic targets for rhythm control.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Concomitant heart failure (HF) poses a particular therapeutic challenge and is associated with prolonged atrial electrical refractoriness compared with non-failing hearts. We hypothesized that downregulation of atrial repolarizing TREK-1 (K2.

KCC2 knockdown impairs glycinergic synapse maturation in cultured spinal cord neurons.

Synaptic inhibition in the spinal cord is mediated mainly by strychnine-sensitive glycine (GlyRs) and by γ-aminobutyric acid type A receptors (GABAAR). During neuronal maturation, neonatal GlyRs containing α2 subunits are replaced by adult-type GlyRs harboring α1 and α3 subunits. At the same time period of postnatal development, the transmembrane chloride gradient is changed due to increased expression of the potassium-chloride cotransporter (KCC2), thereby shifting the GABA- and glycine-mediated synaptic currents from mostly excitatory depolarization to inhibitory hyperpolarization.

Mechanism and functional impact of CD40 ligand-induced von Willebrand factor release from endothelial cells.

Co-stimulation via CD154 binding to CD40, pivotal for both innate and adaptive immunity, may also link haemostasis to vascular remodelling. Here we demonstrate that human platelet-bound or recombinant soluble CD154 (sCD154) elicit the release from and tethering of ultra-large (UL) von Willebrand factor (vWF) multimers to the surface of human cultured endothelial cells (ECs) exposed to shear stress. This CD40-mediated ULVWF multimer release from the Weibel-Palade bodies was triggered by consecutive activation of TRAF6, the tyrosine kinase c-Src and phospholipase Cγ1 followed by inositol-1,4,5 trisphosphate-mediated calcium mobilisation.

The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel.

Background: Inherited arrhythmias were originally considered isolated electrical defects. There is growing evidence that ion channel dysfunction also contributes to myocardial disorders, but genetic overlap has not been reported for sinus node dysfunction (SND) and noncompaction cardiomyopathy (NCCM).

Objectives: The study sought to investigate a familial electromechanical disorder characterized by SND and NCCM, and to identify the underlying genetic basis.

MiR-134-dependent regulation of Pumilio-2 is necessary for homeostatic synaptic depression.

Neurons employ a set of homeostatic plasticity mechanisms to counterbalance altered levels of network activity. The molecular mechanisms underlying homeostatic plasticity in response to increased network excitability are still poorly understood. Here, we describe a sequential homeostatic synaptic depression mechanism in primary hippocampal neurons involving miRNA-dependent translational regulation.

Synthetic Aβ oligomers (Aβ(1-42) globulomer) modulate presynaptic calcium currents: prevention of Aβ-induced synaptic deficits by calcium channel blockers.

Alzheimer's disease is accompanied by increased brain levels of soluble amyloid-β (Aβ) oligomers. It has been suggested that oligomers directly impair synaptic function, thereby causing cognitive deficits in Alzheimer's disease patients. Recently, it has been shown that synthetic Aβ oligomers directly modulate P/Q-type calcium channels, possibly leading to excitotoxic cascades and subsequent synaptic decline.

Establishment of a secondary screening assay for P/Q-type calcium channel blockers.

Development of calcium channel blockers is attractive, but has in the past been hampered by lack of high throughput electrophysiological technology. This limitation has been overcome by the implementation of automated patch clamp systems that allow identification of state-dependent compounds, which preferentially target pathologically overactive channels. We recently presented a fluorescence-based high-throughput screen for P/Q-type calcium channels followed by automated electrophysiology.

Altered HCN4 channel C-linker interaction is associated with familial tachycardia-bradycardia syndrome and atrial fibrillation.

Aims: HCN4 channels are involved in generation, regulation, and stabilization of heart rhythm and channel dysfunction is associated with inherited sinus bradycardia. We asked whether dysfunctional HCN4 channels also contribute to the generation of cardiac tachyarrhythmias.

Methods And Results: In a candidate gene approach, we screened 422 patients with atrial and/or ventricular tachyarrhythmias and detected a novel HCN4 gene mutation that replaced the positively charged lysine 530 with an asparagine (HCN4-K530N) in a highly conserved region of the C-linker.

Synaptic glutamate release is modulated by the Na+ -driven Cl-/HCO₃⁻ exchanger Slc4a8.

On the one hand, neuronal activity can cause changes in pH; on the other hand, changes in pH can modulate neuronal activity. Consequently, the pH of the brain is regulated at various levels. Here we show that steady-state pH and acid extrusion were diminished in cultured hippocampal neurons of mice with a targeted disruption of the Na(+)-driven Cl(-)/HCO(3)(-) exchanger Slc4a8.

Age dependence of excitatory-inhibitory balance following stroke.

The mechanisms which mediate cortical map plasticity and functional recovery following stroke remain a matter of debate. Readjustment of the excitatory-inhibitory balance may support cortical map plasticity in perilesional areas. Here we studied cortical net inhibition in the vicinity of photothrombotically-induced cortical lesions in young adult (3 months) and aged (24 months) male rats.

Tonic GABAergic control of mouse dentate granule cells during postnatal development.

The dentate gyrus is the main hippocampal input structure receiving strong excitatory cortical afferents via the perforant path. Therefore, inhibition at this 'hippocampal gate' is important, particularly during postnatal development, when the hippocampal network is prone to seizures. The present study describes the development of tonic GABAergic inhibition in mouse dentate gyrus.

cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control.

Background: HCN channels activate the pacemaker current I(f), which is thought to contribute significantly to generation and regulation of heart rhythm. HCN4 represents the dominant isotype in the sinoatrial node and binding of cAMP was suggested to be necessary for autonomic heart rate regulation.

Methods And Results: In a candidate gene approach, a heterozygous insertion of 13 nucleotides in exon 6 of the HCN4 gene leading to a truncated cyclic nucleotide-binding domain was identified in a 45-year-old woman with sinus bradycardia.

Region- and pattern-specific effects of glutamate uptake blockers on epileptiform activity in rat brain slices.

Many epileptic syndromes develop into pharmaco-resistant forms, calling for the development of new anticonvulsant strategies. The transmitter glutamate serves a double role as excitatory transmitter and as precursor for GABA, thus interfering with glutamate uptake may therefore exert complex effects on excitation-inhibition-balance in epileptic networks. In the present study we tested the effect of two different glutamate uptake blockers on acutely induced epileptiform activity in hippocampal-entorhinal cortex slices from adult rats: dihydrokainate (DHK) which blocks predominantly glial glutamate uptake, and threo-beta-benzyloxyaspartic acid (TBOA) which blocks both glial and neuronal glutamate uptake.

Fast homeostatic plasticity of inhibition via activity-dependent vesicular filling.

Synaptic activity in the central nervous system undergoes rapid state-dependent changes, requiring constant adaptation of the homeostasis between excitation and inhibition. The underlying mechanisms are, however, largely unclear. Chronic changes in network activity result in enhanced production of the inhibitory transmitter GABA, indicating that presynaptic GABA content is a variable parameter for homeostatic plasticity.

Compensatory increase in P/Q-calcium current-mediated synaptic transmission following chronic block of N-type channels.

Synaptic transmission is triggered by presynaptic calcium influx through voltage-gated calcium channels. Axon terminals of central neurons express a diverse set of homologous calcium channels, giving rise to P/Q-, N-, and R-type calcium currents. The relative contribution of these components to presynaptic calcium signalling is heterogeneous and incompletely understood.

Age-related decline of functional inhibition in rat cortex.

Recent studies with functional magnetic brain imaging showed different task-related patterns of brain activation and deactivation in aged as compared to young healthy subjects. We hypothesized that these changes of brain activation patterns might be due to age-dependent changes of neuronal excitability. Therefore, we experimentally studied the functional cortical inhibition by paired pulse stimulation in brain slices of young adult (3 months), aged adult (24 months) and old (36 months) male rats.