Background/Aims: Dysferlin plays a decisive role in calcium-dependent membrane repair in myocytes. Mutations in the encoding DYSF gene cause a number of myopathies, e.g. limb-girdle muscular ...dystrophy type 2B (LGMD2B). Besides skeletal muscle degenerative processes, dysferlin deficiency is also associated with cardiac complications. Thus, both LGMD2B patients and dysferlin-deficient mice develop a dilated cardiomyopathy. We and others have recently reported that dystrophin-deficient ventricular cardiomyocytes from mouse models of Duchenne muscular dystrophy show significant abnormalities in voltage-dependent ion channels, which may contribute to the pathophysiology in dystrophic cardiomyopathy. The aim of the present study was to investigate if dysferlin, like dystrophin, is a regulator of cardiac ion channels. Methods and Results: By using the whole cell patch-clamp technique, we compared the properties of voltage-dependent calcium and sodium channels, as well as action potentials in ventricular cardiomyocytes isolated from the hearts of normal and dysferlin-deficient (dysf) mice. In contrast to dystrophin deficiency, the lack of dysferlin did not impair the ion channel properties and left action potential parameters unaltered. In connection with normal ECGs in dysf mice these results suggest that dysferlin deficiency does not perturb cardiac electrophysiology. Conclusion: Our study demonstrates that dysferlin does not regulate cardiac voltage-dependent ion channels, and implies that abnormalities in cardiac ion channels are not a universal characteristic of all muscular dystrophy types.
Background/Aims: Cell transplantation into the heart is a new therapy after myocardial infarction. Its success, however, is impeded by poor donor cell survival and by limited transdifferentiation of ...the transplanted cells into functional cardiomyocytes. A promising strategy to overcome these problems is the induction of cardiomyogenic properties in donor cells by small molecules. Methods: Here we studied cardiomyogenic effects of the small molecule compound cardiogenol C (CgC), and structural derivatives thereof, on lineage-committed progenitor cells by various molecular biological, biochemical, and functional assays. Results: Treatment with CgC up-regulated cardiac marker expression in skeletal myoblasts. Importantly, the compound also induced cardiac functional properties: first, cardiac-like sodium currents in skeletal myoblasts, and secondly, spontaneous contractions in cardiovascular progenitor cell-derived cardiac bodies. Conclusion: CgC induces cardiomyogenic function in lineage-committed progenitor cells, and can thus be considered a promising tool to improve cardiac repair by cell therapy.
As the main input nucleus of the basal ganglia, the striatum plays a central role in planning, control, and execution of movement and motor skill learning. More than 90% of striatal neurons, ...so-called medium spiny neurons (MSN), are GABAergic projection neurons, innervating primarily the substantia nigra pars reticulata or the globus pallidus internus. The remaining neurons are GABAergic and cholinergic interneurons, synchronizing and controlling striatal output by reciprocal connections with MSN. Besides prominent local cholinergic influence, striatal function is globally regulated by dopamine (DA) from the nigrostriatal pathway. Little is known about whether DA depletion, as occurs in Parkinson's disease, affects the activity of striatal interneurons. Here we focused on neuropeptide Y (NPY)-expressing interneurons, which are among the major subgroups of GABAergic interneurons in the striatum. We investigated the effects of striatal DA depletion on GABAergic transmission in NPY interneurons by electrophysiologically recording GABAergic spontaneous (s) and miniature (m) inhibitory postsynaptic currents (IPSCs) in identified NPY interneurons in slices from 6-hydroxydopamine (6-OHDA)- and vehicle-injected transgenic NPY-humanized
green fluorescent protein (hrGFP) mice with the whole cell patch-clamp technique. We report a significant increase in sIPSC and mIPSC frequency as well as the occurrence of giant synaptic and burst sIPSCs in the 6-OHDA group, suggesting changes in GABAergic circuit activity and synaptic transmission. IPSC kinetics remained unchanged, pointing to mainly presynaptic changes in GABAergic transmission. These results show that chronic DA depletion following 6-OHDA injection causes activity-dependent and -independent increase of synaptic GABAergic inhibition onto striatal NPY interneurons, confirming their involvement in the functional impairments of the DA-depleted striatum.
Neuropeptide Y (NPY) interneurons regulate the function of striatal projection neurons and are upregulated upon dopamine depletion in the striatum. Here we investigated how dopamine depletion affects NPY circuits and show electrophysiologically that it leads to the occurrence of giant synaptic and burst GABAergic spontaneous inhibitory postsynaptic currents (IPSCs) and to an activity-independent increase in GABAergic miniature IPSC frequency in NPY neurons. We suggest that degeneration of dopaminergic terminals in the striatum causes functional changes in striatal GABAergic function.
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•PDS arise in the course of experimentally-provoked seizure-like activity.•PDS can also be induced by cellular processes typical of seizure aftermath.•PDS closely resemble modulatory ...electrical activity patterns in neurodevelopment.•L-type calcium channels are essential for formation of these PDS.•L-type calcium channels potentially a valuable target to interfere with PDS effects.
Since their discovery in the 1960s, the term paroxysmal depolarization shift (PDS) has been applied to a wide variety of reinforced neuronal discharge patterns. Occurrence of PDS as cellular correlates of electrographic spikes during latent phases of insult-induced rodent epilepsy models and their resemblance to giant depolarizing potentials (GDPs) nourished the idea that PDS may be involved in epileptogenesis. Both GDPs and – in analogy – PDS may lead to progressive changes of neuronal properties by generation of pulsatile intracellular Ca2+ elevations. Herein, a key element is the gating of L-type voltage gated Ca2+ channels (LTCCs, Cav1.x family), which may convey Ca2+ signals to the nucleus. Accordingly, the present study investigates various insult-associated neuronal challenges for their propensities to trigger PDS in a LTCC-dependent manner. Our data demonstrate that diverse disturbances of neuronal function are variably suited to induce PDS-like events, and the contribution of LTCCs is essential to evoke PDS in rat hippocampal neurons that closely resemble GDPs. These PDS appear to be initiated in the dendritic sub-compartment. Their morphology critically depends on the position of recording electrodes and on their rate of occurrence. These results provide novel insight into induction mechanisms, origin, variability, and co-existence of PDS with other discharge patterns and thereby pave the way for future investigations regarding the role of PDS in epileptogenesis.
Echocardiography provides recordings of the heart chamber size and function and is a central tool for non-invasive diagnosis of heart diseases. It produces high-dimensional video data with ...substantial stochasticity in the measurements, which frequently prove difficult to interpret. To address this challenge, we propose an automated framework to enable the inference of a high resolution personalized 4D (3D plus time) surface mesh of the cardiac structures from 2D echocardiography video data. Inferring such shape models arises as a key step towards accurate personalized simulation that enables an automated assessment of the cardiac chamber morphology and function. The proposed method is trained using only unpaired echocardiography and heart mesh videos to find a mapping between these distinct visual domains in a self-supervised manner. The resulting model produces personalized 4D heart meshes, which exhibit a high correspondence with the input echocardiography videos. Furthermore, the 4D heart meshes enable the automatic extraction of echocardiographic variables, such as ejection fraction, myocardial muscle mass, and volumetric changes of chamber volumes over time with high temporal resolution.
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•The visualization of patient-specific dynamic 3D cardiac models is of fundamental practical importance in precision medicine.•Echocardiography combines low-cost portable instrumentation and rapid image acquisition without the risks of ionizing radiation.•Novel model to infer high-resolution surface heart mesh videos from 2D echocardiogram video data.
Ivabradine blocks hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels, thereby lowering the heart rate, an action that is used clinically for the treatment of heart failure and angina ...pectoris. We and others have shown previously that ivabradine, in addition to its HCN channel blocking activity, also inhibits voltage-gated Na channels in vitro at concentrations that may be clinically relevant. Such action may reduce conduction velocity in cardiac atria and ventricles.
Here, we explore the effect of administration of ivabradine on parameters of ventricular conduction and repolarization in the surface ECG of anesthetized mice. We found that 5 min after i.p. administration of 10 mg/kg ivabradine spontaneous heart rate had declined by ~13%, which is within the range observed in human clinical studies. At the same time a significant increase in QRS duration by ~18% was observed, suggesting a reduction in ventricular conduction velocity. During transesophageal pacing at heart rates between 100 and 220 beats/min there was no obvious rate-dependence of ivabradine–induced QRS prolongation. On the other hand, ivabradine produced substantial rate-dependent slowing of AV nodal conduction. We conclude that ivabradine prolongs conduction in the AV-node and in the ventricles in vivo.
The striatum is the main input nucleus of the basal ganglia, mediating motor and cognitive functions. Striatal projection neurons are GABAergic medium spiny neurons (MSN), expressing either the ...dopamine receptor type 1 (D
-R MSN) and forming the direct, movement-promoting pathway, or dopamine receptor type 2 (D
-R MSN), forming the indirect movement-suppressing pathway. Locally, activity and synchronization of MSN are modulated by several subtypes of GABAergic and cholinergic interneurons. Overall, GABAergic circuits in the striatum remain poorly characterized, and little is known about the intrastriatal connectivity of interneurons and the distribution of GABA
receptor (GABA
R) subtypes, distinguished by their subunit composition, in striatal synapses. Here, by using immunofluorescence in mouse tissue, we investigated the distribution of GABA
Rs containing the α
, α
, or α
subunit in perisomatic synapses of striatal MSN and interneurons, as well as the innervation pattern of D
R- and D
R-MSN soma and axonal initial segment (AIS) by GABAergic and cholinergic interneurons. Our results show that perisomatic GABAergic synapses of D
R- and D
R-MSN contain the GABA
R α
and/or α
subunits, but not the α
subunit; D
R-MSN have significantly more α
-GABA
Rs on their soma than D
R-MSN. Further, interneurons have few perisomatic synapses containing α
-GABA
Rs, whereas α
-GABA
Rs (along with the α
-GABA
Rs) are abundant in perisomatic synapses of CCK
, NPY
/SOM
, and vAChT
interneurons. Each MSN and interneuron population analyzed received a distinct pattern of GABAergic and cholinergic innervation, complementing this postsynaptic heterogeneity. In conclusion, intra-striatal GABAergic circuits are distinguished by cell-type specific innervation patterns, differential expression and postsynaptic targeting of GABA
R subtypes.
Kir2.x channels in ventricular cardiomyocytes (most prominently Kir2.1) account for the inward rectifier potassium current I
K1
, which controls the resting membrane potential and the final phase of ...action potential repolarization. Recently it was hypothesized that the dystrophin-associated protein complex (DAPC) is important in the regulation of Kir2.x channels. To test this hypothesis, we investigated potential I
K1
abnormalities in dystrophin-deficient ventricular cardiomyocytes derived from the hearts of Duchenne muscular dystrophy mouse models. We found that I
K1
was substantially diminished in dystrophin-deficient cardiomyocytes when compared to wild type myocytes. This finding represents the first functional evidence for a significant role of the DAPC in the regulation of Kir2.x channels.
The striatum is the main input nucleus of the basal ganglia, mediating motor and cognitive functions. Striatal projection neurons are GABAergic medium spiny neurons (MSN), expressing either the ...dopamine receptor type 1 (D1‐R MSN) and forming the direct, movement‐promoting pathway, or dopamine receptor type 2 (D2‐R MSN), forming the indirect movement‐suppressing pathway. Locally, activity and synchronization of MSN are modulated by several subtypes of GABAergic and cholinergic interneurons. Overall, GABAergic circuits in the striatum remain poorly characterized, and little is known about the intrastriatal connectivity of interneurons and the distribution of GABAA receptor (GABAAR) subtypes, distinguished by their subunit composition, in striatal synapses. Here, by using immunofluorescence in mouse tissue, we investigated the distribution of GABAARs containing the α1, α2, or α3 subunit in perisomatic synapses of striatal MSN and interneurons, as well as the innervation pattern of D1R‐ and D2R‐MSN soma and axonal initial segment (AIS) by GABAergic and cholinergic interneurons. Our results show that perisomatic GABAergic synapses of D1R‐ and D2R‐MSN contain the GABAAR α1 and/or α2 subunits, but not the α3 subunit; D2R‐MSN have significantly more α1‐GABAARs on their soma than D1R‐MSN. Further, interneurons have few perisomatic synapses containing α2‐GABAARs, whereas α3‐GABAARs (along with the α1‐GABAARs) are abundant in perisomatic synapses of CCK+, NPY+/SOM+, and vAChT+ interneurons. Each MSN and interneuron population analyzed received a distinct pattern of GABAergic and cholinergic innervation, complementing this postsynaptic heterogeneity. In conclusion, intra‐striatal GABAergic circuits are distinguished by cell‐type specific innervation patterns, differential expression and postsynaptic targeting of GABAAR subtypes.
The distribution of GABAARs containing the α1, α2, and α3 subunit in perisomatic GABAergic synapses was investigated in D1R‐ and D2R‐MSN, GABAergic (PV+, CCK+, NPY+, and SOM+) and cholinergic interneurons in the dorsolateral striatum. In D1R‐ and D2R‐MSN the majority of synapses contained GABAAR α1 and α2 subunits, whereas the GABAAR α3 subunit is specific for certain subpopulations of striatal interneurons. In turn, perisomatic synapses originate from different sources, indicating that the expression of GABAARs is not random, but correlates with the expression of specific neurochemical markers distinguishing specific GABAergic circuits in the dorsal striatum.
Ibogaine is a plant alkaloid used as anti-addiction drug in dozens of alternative medicine clinics worldwide. Recently, alarming reports of life-threatening cardiac arrhythmias and cases of sudden ...death associated with the ingestion of ibogaine have accumulated. Using whole-cell patch clamp recordings, we assessed the effects of ibogaine and its main metabolite noribogaine on action potentials in human ventricular-like cardiomyocytes derived from induced pluripotent stem cells. Therapeutic concentrations of ibogaine and its long-lived active metabolite noribogaine significantly retarded action potential repolarization in human cardiomyocytes. These findings represent the first experimental proof that ibogaine application entails a cardiac arrhythmia risk for humans. In addition, they explain the clinically observed delayed incidence of cardiac adverse events several days after ibogaine intake. We conclude that therapeutic concentrations of ibogaine retard action potential repolarization in the human heart. This may give rise to a prolongation of the QT interval in the electrocardiogram and cardiac arrhythmias.
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