Funktionelle Analyse des Cav2.3 Kalziumkanals im kardiovaskulären System

Basierend auf transgenen Mausmodelle, die einen Einblick in Ätiologie und Pathogenese von Kanalkrankheiten ermöglichen, hat sich das Wissen hinsichtlich kardiomyogener Automatizität und Propagation der kardialen Erregung in den letzten Jahren enorm erweitert. Nur vier Vertreter spannungsgesteuerter Kalziumkanäle galten ursprünglich als im Herzen exprimiert (Cav1.3, Cav1.2, Cav3.1 und Cav3.2), deren Ablation bei Cav1.3 und Cav3.1 zu markanten kardialen Phänotypen führte, bei anderen hingegen entweder schon in der frühen Pränatalphase letal war (Cav1.2) oder keinen direkten kardialen Effekt zeigte (Cav3.2). Die vorliegende Arbeit legt eine kardiovaskuläre Charakterisierung Cav2.3 defizienter Mäuse vor, unter Zuhilfenahme molekularbiologischer und elektrophysiologischer Verfahren. Sie zeigt, dass mit Cav2.3 eine bis dahin für die kardiale Erregungsbildung- und Erregungsfortleitung als umstritten eingestufte Kalziumkanaluntereinheit einen wichtigen Beitrag zur funktionellen Integrität des Herzens und des kardiovaskulären Systems beisteuert. Auf molekularbiologischer Ebene konnte gezeigt werden, dass nicht nur unterschiedliche Cav2.3 Spleißvarianten im Mausherzen vorliegen, die v.a. in der Pränatalphase eine entwicklungsabhängige Änderung im Verteilungsmuster aufweisen, sondern auch höhere Transkriptzahlen im Atrium im Vergleich zum Ventrikel vorzufinden sind. Diese Ergebnisse wurden durch funktionelle (MEA) Studien unterstützt, die in isolierten pränatalen Cav2.3(-|-) Herzen nicht nur einen erhöhten Variationskoeffizienten, sondern auch Störungen der kardialen Erregungsausbreitung zeigten. Telemetrische EKG-Aufzeichnungen von Cav2.3(-|-) Mäusen konnten weiterhin belegen, dass auch in adulten Tieren Arrhythmien vorliegen, die sowohl Störungen der atrialen Erregung, der AV-Überleitung und der ventrikulären Erregungsausbreitung beinhalten. Die zeitbasierte Analyse der Herzfrequenzvariabilität machte deutlich, dass Cav2.3(-|-) Tiere nicht nur eine signifikante Erhöhung des Variationskoeffizienten, sondern auch der Herzfrequenz aufweisen. Mittels eines pharmakologischen autonomen Blocks stellte sich heraus, dass die erhöhte Herzfrequenz das Resultat eines erhöhten Sympathikotonus ist und auch die AV-Blockbilder waren nach autonomer pharmakologischer Denervation nicht mehr vorzufinden. Damit wurde, bestärkt durch weitere pharmakologische Injektionsexperimente, deutlich, dass Cav2.3 innerhalb des kardiovaskulären Systems sowohl intrinsisch-kardiale, als auch extrinsisch-autonome Aufgaben übernimmt. Die Untersuchung des sympathischen Astes des autonomen Nerven-systems zeigte überraschenderweise eine �Propranololresistenz� in Cav2.3(-|-) Mäusen im Vergleich zu Kontrolltieren, dessen zugrundeliegender Mechanismus und funktionelle Implikation noch ungeklärt ist. Die pharmakologisch induzierbare maximale Herzfrequenzbreite und die Herzreserve weisen eine deutliche Reduktion in Cav2.3(-|-) Tieren auf und müssen in ursächlichem Zusammenhang mit dem signifikant schlechteren Abschneiden Cav2.3 defizienter Mäuse im Laufradexperiment im Vergleich zu Kontrolltieren gesehen werden. Die vorliegende Arbeit stellt dar, dass Cav2.3 in Physiologie und Pathophysiologie des Herzen nicht nur im Erregungsbildungs- und Leitungssystem von Bedeutung ist, sondern auch eine wichtige Funktion bei der autonomen Transmission spielt. Da sich Cav2.3 Transkripte nicht nur im Maus- und Rattenherzen, sondern auch im Herzen großer Säuger (Hausschwein, Mensch) finden ließen, gewinnt Cav2.3 damit auch humanpathophysiologisch Relevanz. Zukünftige Patch-Clamp Studien müssen zeigen, welche Rolle Cav2.3 hierbei auf Einzelzellebene spielt

Measures of Resting State EEG Rhythms for Clinical Trials in Alzheimer’s Disease:Recommendations of an Expert Panel

The Electrophysiology Professional Interest Area (EPIA) and Global Brain Consortium endorsed recommendations on candidate electroencephalography (EEG) measures for Alzheimer's disease (AD) clinical trials. The Panel reviewed the field literature. As most consistent findings, AD patients with mild cognitive impairment and dementia showed abnormalities in peak frequency, power, and "interrelatedness" at posterior alpha (8-12Hz) and widespread delta (<4Hz) and theta (4-8Hz) rhythms in relation to disease progression and interventions. The following consensus statements were subscribed: (1) Standardization of instructions to patients, resting state EEG (rsEEG) recording methods, and selection of artifact-free rsEEG periods are needed; (2) power density and "interrelatedness" rsEEG measures (e.g., directed transfer function, phase lag index, linear lagged connectivity, etc.) at delta, theta, and alpha frequency bands may be use for stratification of AD patients and monitoring of disease progression and intervention; and (3) international multisectoral initiatives are mandatory for regulatory purposes

What Electrophysiology Tells Us About Alzheimer’s Disease::A Window into the Synchronization and Connectivity of Brain Neurons

Electrophysiology provides a real-time readout of neural functions and network capability in different brain states, on temporal (fractions of milliseconds) and spatial (micro, meso, and macro) scales unmet by other methodologies. However, current international guidelines do not endorse the use of electroencephalographic (EEG)/magnetoencephalographic (MEG) biomarkers in clinical trials performed in patients with Alzheimer’s disease (AD), despite a surge in recent validated evidence. This Position Paper of the ISTAART Electrophysiology Professional Interest Area endorses consolidated and translational electrophysiological techniques applied to both experimental animal models of AD and patients, to probe the effects of AD neuropathology (i.e., brain amyloidosis, tauopathy, and neurodegeneration) on neurophysiological mechanisms underpinning neural excitation/inhibition and neurotransmission as well as brain network dynamics, synchronization, and functional connectivity reflecting thalamocortical and cortico-cortical residual capacity. Converging evidence shows relationships between abnormalities in EEG/MEG markers and cognitive deficits in groups of AD patients at different disease stages. The supporting evidence for the application of electrophysiology in AD clinical research as well as drug discovery pathways warrants an international initiative to include the use of EEG/MEG biomarkers in the main multicentric projects planned in AD patients, to produce conclusive findings challenging the present regulatory requirements and guidelines for AD studies

Wenn das Gehirn aus dem Rhythmus kommt

In den vergangenen Jahren hat sich die systemische Neurowissenschaft als zentraler Forschungsbereich etabliert. Die Entstehung und Aufrechterhaltung zentralnervöser Rhythmen ist hierbei von essenzieller Bedeutung und wird intensiv erforscht. Während neurodegenerative und neuropsychiatrische Erkrankungen in ihrer Symptomatik extrem mannigfaltig sein können, scheinen die zugrunde liegenden Dysrhythmien Gemeinsamkeiten aufzuweisen.1 Diese funktionellen Übereinstimmungen zu erforschen, ist nicht nur von Bedeutung für die Grundlagenforschung, sondern auch von klinischer Relevanz und eröffnet neue Perspektiven in der Arzneitherapie. Mit dem septohippokampalen System und dem thalamokortikalen Netzwerk werden im Folgenden zwei neuronale Systeme skizziert, welche unter anderem für beeinträchtigte kognitive Leistungsfähigkeiten bei der Alzheimer-Demenz sowie für alterierte Filterprozesse bei der Schizophrenie maßgeblich verantwortlich sind. Das BfArM betreibt hierzu eigene Forschungsprojekte, die zukünftig helfen werden, die Arzneimittelsicherheit zu verbessern

Translational Brain Rhythmicity – Open Access

It is my distinct honor and privilege to have followedthe invitation to become Founding Editor and Editor-in-Chief (EIC) of Translational Brain Rhythmicity(TBR),an online peer-reviewed open access journal. In my capacity as EIC and on behalf of our Editorial Board members I would like to forward a very warm welcome to you, the readership of our new journal. I would like to take the opportunity to thank our prospective authors, the editors and the anonymous reviewers for their dedication to contribute to the success of Translational Brain Rhythmicity. Neuroscience is an extraordinary, fascinating scientific field composed of numerous subdisciplines such as neuroanatomy, neurochemistry, neuroendocrinology, neuropathology, neurophysiology, neuropharmacology, neurogenetics, molecular neuroscience, cellular neuroscience, behavioral neuroscience, affective neuroscience, system neuroscience, cognitive neuroscience, clinical neuroscience, computational neuroscience, cultural neuroscience, developmental neuroscience, neuroimaging, neuroinformatics, neurolinguistics and many more. However, none of these sub-disciplines remain isolated. Indeed, they all share - to a specific extend -common aspects and are to be investigated considering their interdependence. Translational Brain Rhythmicity covers the functional integration of these subfields and their impact on brain rhythmicity. Research within the last decades has gained tremendous insight into the mechanisms of proper brain function but also pathophysiological aberrations responsible for neurological and neuropsychiatric diseases. Many of these important findings are related to alterations in biochemical pathways, signal transduction cascades and ion channel dysfunction, e.g. channelopathies,suggesting that we already know a lot but clearly not all about the molecular and cellular background of neurological and neuropsychiatric diseases and epileptic disorders. In drug research and development, most novel pharmacotherapeutic approaches and recent interventions are based on molecular and cellular findings in neurons and in many cases these novel approaches have failed to exhibit efficacy/effectiveness and positive benefit-risk ratio in patients following independent scientific assessment of clinical trials. A very prominent example for this development is Alzheimer’s disease in which most Phase III clinical trials failed within the last 10-15 years althoughmany candidates were novel, first-in-class drugs and highly promising due to basic and preclinical research results. This observation clearly tells us that there is much more we have to learn and we are still lacking sufficient information about the higher structural and functional organization of the central nervous system. It feels mandatory to us to overcome the gap between basic neuroscience and system neuroscience and to contribute to the overall understanding of how the brain and its subsystems actually work and interact. This journal is thus dedicated to help unravel the functional interdependence between molecular and cellular neuronal processes and their impact on neuronal ensemble activity, i.e. the physiology and pathophysiology of neuronal circuitries and networks. Importantly, studies presented in Translational Brain Rhythmicity are not restricted to the mammalian or human brain but can also include CNS rhythmicity studies on brains or nervous systems of other taxa as long as they contribute to the overall understanding of highly differentiated CNS structures, neural circuitry rhythmicity and oscillations. The journal is specifically dedicated to translation of molecular, cellular and systemic neural experimental approaches from animal models to human neurological and neuropsychiatric diseases. Methodologically, the journal is not only limited to cellular and systemic electrophysiological in-vitro and in-vivo techniques, but also to molecular, genetic and behavioral approaches that affect neuronal activity on the cellular and thus also the circuitry and network level. We also welcome submission of clinical trial results of CNS drugs that affect or exhibit modulation of brain dysrhythmia. As a prominent forum of scientific exchange, Translational Brain Rhythmicity encourages submission of different manuscripts formats, e.g. full length original articles, short research letters, review articles, methodological manuscripts, case reports, clinical trial outcome reports, best-practice guides, commentaries, controversies, congress reports, and letters to the editor. The Editorial Board of Translational Brain Rhythmicity ensures application of highest scientific standards confirming to the strict international peer-reviewing processes and editorial standards of the scientific community and Translational Brain Rhythmicity is in line with current COPE regulations. Translational Brain Rhythmicity is published six times a year. In order to spread scientific information fast, the reviewing process is aimed to last no longer than 2 months. In order to disseminate outstanding manuscripts and their findings rapidly, a fast-track reviewing system is installed that guarantees online publication within two weeks. This approach enables Translational Brain Rhythmicity to timely react on fast, new developments in the field. If you would like to push a specific topic in Translational Brain Rhythmicitywe strongly encourage you to submit proposals for specials issues in which you can serve as a guest editor. Besides, the editorial board of Translational Brain Rhythmicity will periodically announce calls for special issues on current hot topics. Finally, I strongly encourage you to submit your valuable research to Translational Brain Rhythmicity via [email protected]. We hope that you will find Translational Brain Rhythmicity a useful and informative outlet for your research and a valuable source of information, evidence and critical debate

Breeding of Cav2.3 deficient mice reveals Mendelian inheritance in contrast to complex inheritance in Cav3.2 null mutant breeding

High voltage-activated Cav2.3 R-type Ca2+ channels and low voltage-activated Cav3.2 T-type Ca2+ channels were reported to be involved in numerous physiological and pathophysiological processes. Many of these findings are based on studies in Cav2.3 and Cav3.2 deficient mice. Recently, it has been proposed that inbreeding of Cav2.3 and Cav3.2 deficient mice exhibits significant deviation from Mendelian inheritance and might be an indication for potential prenatal lethality in these lines. In our study, we analyzed 926 offspring from Cav3.2 breedings and 1142 offspring from Cav2.3 breedings. Our results demonstrate that breeding of Cav2.3 deficient mice shows typical Mendelian inheritance and that there is no indication of prenatal lethality. In contrast, Cav3.2 breeding exhibits a complex inheritance pattern. It might be speculated that the differences in inheritance, particularly for Cav2.3 breeding, are related to other factors, such as genetic specificities of the mutant lines, compensatory mechanisms and altered sperm activity

High-dose maternal folic acid supplementation before conception impairs reversal learning in offspring mice

Maternal folic acid (FA) supplementation prior to and during gestation is recommended for the prevention of neural tube closure defects in the developing embryo. Prior studies, however, suggested that excessive FA supplementation during gestation can be associated with toxic effects on the developing organism. Here, we address whether maternal dietary folic acid supplementation at 40 mg/kg chow (FD), restricted to a period prior to conception, affects neurobehavioural development in the offspring generation. Detailed behavioural analyses showed reversal learning impairments in the Morris water maze in offspring derived from dams exposed to FD prior to conceiving. Furthermore, offspring of FD dams showed minor and transient gene expression differences relative to controls. Our data suggest that temporary exposure of female germ cells to FD is sufficient to cause impaired cognitive flexibility in the subsequent generation