Chronic homocysteine exposure causes changes in the intrinsic electrophysiological properties of cultured hippocampal neurons

Homocystinuria is an inborn error of metabolism characterized by plasma homocysteine levels up to 500μM, premature vascular events and mental retardation. Mild elevations of homocysteine plasma levels up to 25μM, which are common in the general population, are associated with vascular disease, cognitive impairment and neurodegeneration. Several mechanisms of homocysteine neurotoxicity have been investigated. However, information on putative effects of hyperhomocysteinemia on the electrophysiology of neurons is limited. To screen for such effects, we examined primary cultures of mouse hippocampal neurons with the whole-cell patch-clamp technique. Homocysteine was applied intracellularly (100μM), or cell cultures were incubated with 100μM homocysteine for 24h. Membrane voltage was measured in current-clamp mode, and action potential firing was induced with short and prolonged current injections. Single action potentials induced by short current injections (5ms) were not altered by acute application or incubation of homocysteine. When we elicited trains of action potentials with prolonged current injections (200ms), a broadening of action potentials during repetitive firing was observed in control neurons. This spike broadening was unaltered by acute application of homocysteine. However, it was significantly diminished when incubation with homocysteine was extended to 24h prior to recording. Furthermore, the number of action potentials elicited by low current injections was reduced after long-term incubation with homocysteine, but not by the acute application. After 24h of homocysteine incubation, the input resistance was reduced which might have contributed to the observed alterations in membrane excitability. We conclude that homocysteine exposure causes changes in the intrinsic electrophysiological properties of cultured hippocampal neurons as a mechanism of neurological symptoms of hyperhomocysteinemi

Lithologic and electrometric characteristic of productive layers of the gurarinckiy-sobolinniy deposit low-chalky adjourments

The construction of abnormal geochemical fields accompanying gold mineralization is investigated; criteria of its quantitative estimation are developed. Orderliness estimation methods of geochemical field abnormal structures and intensity of hydrothermal process are offered. Dependence between quantitative parameters of these structures and scales of gold mineralization is established. Estimation possibility of deposits and ore fields erosive section by parameter values of abnormal geochemical fields is shown

Interactive cohort exploration for spinocerebellar ataxias using synthetic cohort data for visualization

Motivation: Visualization of data is a crucial step to understanding and deriving hypotheses from clinical data. However, for clinicians, visualization often comes with great effort due to the lack of technical knowledge about data handling and visualization. The application offers an easy-to-use solution with an intuitive design that enables various kinds of plotting functions. The aim was to provide an intuitive solution with a low entrance barrier for clinical users. Little to no onboarding is required before creating plots, while the complexity of questions can grow up to specific corner cases. To allow for an easy start and testing with SCAview, we incorporated a synthetic cohort dataset based on real data of rare neurological movement disorders: the most common autosomal-dominantly inherited spinocerebellar ataxias (SCAs) type 1, 2, 3, and 6 (SCA1, 2, 3 and 6). Methods: We created a Django-based backend application that serves the data to a React-based frontend that uses Plotly for plotting. A synthetic cohort was created to deploy a version of SCAview without violating any data protection guidelines. Here, we added normal distributed noise to the data and therefore prevent re-identification while keeping distributions and general correlations. Results: This work presents SCAview, an user-friendly, interactive web-based service that enables data visualization in a clickable interface allowing intuitive graphical handling that aims to enable data visualization in a clickable interface. The service is deployed and can be tested with a synthetic cohort created based on a large, longitudinal dataset from observational studies in the most common SCAs

Impaired D-Serine-Mediated cotransmission mediates cognitive dysfunction in epilepsy

The modulation of synaptic plasticity by NMDA receptor (NMDAR)-mediated processes is essential for many forms of learning and memory. Activation of NMDARs by glutamate requires the binding of a coagonist to a regulatory site of the receptor. In many forebrain regions, this coagonist is D-serine. Here, we show that experimental epilepsy in rats is associated with a reduction in the CNS levels of D-serine, which leads to a desaturation of the coagonist binding site of synaptic and extrasynaptic NMDARs. In addition, the subunit composition of synaptic NMDARs changes in chronic epilepsy. The desaturation of NMDARs causes a deficit in hippocampal long-term potentiation, which can be rescued with exogenously supplied D-serine. Importantly, exogenous D-serine improves spatial learning in epileptic animals. These results strongly suggest that D-serine deficiency is important in the amnestic symptoms of temporal lobe epilepsy. Our results point to a possible clinical utility of D-serine to alleviate these disease manifestations

Impaired D-Serine-Mediated cotransmission mediates cognitive dysfunction in epilepsy

The modulation of synaptic plasticity by NMDA receptor (NMDAR)-mediated processes is essential for many forms of learning and memory. Activation of NMDARs by glutamate requires the binding of a coagonist to a regulatory site of the receptor. In many forebrain regions, this coagonist is D-serine. Here, we show that experimental epilepsy in rats is associated with a reduction in the CNS levels of D-serine, which leads to a desaturation of the coagonist binding site of synaptic and extrasynaptic NMDARs. In addition, the subunit composition of synaptic NMDARs changes in chronic epilepsy. The desaturation of NMDARs causes a deficit in hippocampal long-term potentiation, which can be rescued with exogenously supplied D-serine. Importantly, exogenous D-serine improves spatial learning in epileptic animals. These results strongly suggest that D-serine deficiency is important in the amnestic symptoms of temporal lobe epilepsy. Our results point to a possible clinical utility of D-serine to alleviate these disease manifestations

Loss of β 1 accessory Na + channel subunits causes failure of carbamazepine, but not of lacosamide, in blocking high‐frequency firing via differential effects on persistent Na + currents

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94523/1/j.1528-1167.2012.03675.x.pd

Mechanisms of noncovalent β subunit regulation of NaV channel gating

Voltage-gated Na(+) (NaV) channels comprise a macromolecular complex whose components tailor channel function. Key components are the non-covalently bound β1 and β3 subunits that regulate channel gating, expression, and pharmacology. Here, we probe the molecular basis of this regulation by applying voltage clamp fluorometry to measure how the β subunits affect the conformational dynamics of the cardiac NaV channel (NaV1.5) voltage-sensing domains (VSDs). The pore-forming NaV1.5 α subunit contains four domains (DI-DIV), each with a VSD. Our results show that β1 regulates NaV1.5 by modulating the DIV-VSD, whereas β3 alters channel kinetics mainly through DIII-VSD interaction. Introduction of a quenching tryptophan into the extracellular region of the β3 transmembrane segment inverted the DIII-VSD fluorescence. Additionally, a fluorophore tethered to β3 at the same position produced voltage-dependent fluorescence dynamics strongly resembling those of the DIII-VSD. Together, these results provide compelling evidence that β3 binds proximally to the DIII-VSD. Molecular-level differences in β1 and β3 interaction with the α subunit lead to distinct activation and inactivation recovery kinetics, significantly affecting NaV channel regulation of cell excitability

SCAview: an Intuitive Visual Approach to the Integrative Analysis of Clinical Data in Spinocerebellar Ataxias

With SCAview, we present a prompt and comprehensive tool that enables scientists to browse large datasets of the most common spinocerebellar ataxias intuitively and without technical effort. Basic concept is a visualization of data, with a graphical handling and filtering to select and define subgroups and their comparison. Several plot types to visualize all data points resulting from the selected attributes are provided. The underlying synthetic cohort is based on clinical data from five different European and US longitudinal multicenter cohorts in spinocerebellar ataxia type 1, 2, 3, and 6 (SCA1, 2, 3, and 6) comprising > 1400 patients with overall > 5500 visits. First, we developed a common data model to integrate the clinical, demographic, and characterizing data of each source cohort. Second, the available datasets from each cohort were mapped onto the data model. Third, we created a synthetic cohort based on the cleaned dataset. With SCAview, we demonstrate the feasibility of mapping cohort data from different sources onto a common data model. The resulting browser-based visualization tool with a thoroughly graphical handling of the data offers researchers the unique possibility to visualize relationships and distributions of clinical data, to define subgroups and to further investigate them without any technical effort. Access to SCAview can be requested via the Ataxia Global Initiative and is free of charge