Control of neuronal ion channel function by glycogen synthase kinase-3: new prospective for an old kinase

Glycogen synthase kinase 3 (GSK-3) is an evolutionarily conserved multifaceted ubiquitous enzyme. In the central nervous system (CNS), GSK-3 acts through an intricate network of intracellular signaling pathways culminating in a highly divergent cascade of phosphorylations that control neuronal function during development and adulthood. Accumulated evidence indicates that altered levels of GSK-3 correlate with maladaptive plasticity of neuronal circuitries in psychiatric disorders, addictive behaviors, and neurodegenerative diseases, and pharmacological interventions known to limit GSK-3 can counteract some of these deficits. Thus, targeting the GSK-3 cascade for therapeutic interventions against this broad spectrum of brain diseases has raised a tremendous interest. Yet, the multitude of GSK-3 downstream effectors poses a substantial challenge in the development of selective and potent medications that could efficiently block or modulate the activity of this enzyme. Although the full range of GSK-3 molecular targets are far from resolved, exciting new evidence indicates that ion channels regulating excitability, neurotransmitter release, and synaptic transmission, which ultimately contribute to the mechanisms underling brain plasticity and higher level cognitive and emotional processing, are new promising targets of this enzyme. Here, we will revise this new emerging role of GSK-3 in controling the activity of voltage-gated Na(+), K(+), Ca(2+) channels and ligand-gated glutamate receptors with the goal of highlighting new relevant endpoints of the neuronal GSK-3 cascade that could provide a platform for a better understanding of the mechanisms underlying the dysfunction of this kinase in the CNS and serve as a guidance for medication development against the broad range of GSK-3-linked human diseases

Improved Methods for Fluorescence Microscopy Detection of Macromolecules at the Axon Initial Segment

The axonal initial segment (AIS) is the subcellular compartment required for initiation of the action potential in neurons. Scaffolding and regulatory proteins at the AIS cluster with ion channels ensuring the integrity of electrical signaling. Interference with the configuration of this protein network can lead to profound effects on neuronal polarity, excitability, cell-to-cell connectivity and brain circuit plasticity. As such, the ability to visualize AIS components with precision provides an invaluable opportunity for parsing out key molecular determinants of neuronal function. Fluorescence-based immunolabeling is a sensitive method for morphological and molecular characterization of fine structures in neurons. Yet, even when combined with confocal microscopy, detection of AIS elements with immunofluorescence has been limited by the loss of antigenicity caused by fixative materials. This technical barrier has posed significant limitations in detecting AIS components alone or in combination with other markers. Here, we designed improved protocols targeted to confocal immunofluorescence detection of the AIS marker fibroblast growth factor 14 (FGF14) in combination with the cytoskeletal-associated protein Ankyrin-G, the scaffolding protein βIV-spectrin, voltage-gated Na+ (Nav) channels (especially the Nav1.6 isoform) and critical cell type-specific neuronal markers such as parvalbumin, calbindin, and NeuN in the mouse brain. Notably, we demonstrate that intracardiac perfusion of animals with a commercially available solution containing 1% formaldehyde and 0.5% methanol, followed by brief fixation with cold acetone is an optimal and sensitive protocol for FGF14 and other AIS marker detection that guarantees excellent tissue integrity. With variations in the procedure, we also significantly improved the detection of Nav1.6, a Nav isoform known for its fixative-sensitivity. Overall, this study provides an ensemble of immunohistochemical recipes that permit excellent staining of otherwise invisible molecules within well-preserved tissue architecture. While improving the specific investigation of AIS physiology and cell biology, our thorough study can also serve as a roadmap for optimizing immunodetection of other fixative-sensitive proteins expanding the repertoire of enabling methods for brain studies

Spectral calibration of exponential Lévy Models [2]

The calibration of financial models has become rather important topic in recent years mainly because of the need to price increasingly complex options in a consistent way. The choice of the underlying model is crucial for the good performance of any calibration procedure. Recent empirical evidences suggest that more complex models taking into account such phenomenons as jumps in the stock prices, smiles in implied volatilities and so on should be considered. Among most popular such models are Levy ones which are on the one hand able to produce complex behavior of the stock time series including jumps, heavy tails and on other hand remain tractable with respect to option pricing. The work on calibration methods for financial models based on Lévy processes has mainly focused on certain parametrisations of the underlying Lévy process with the notable exception of Cont and Tankov (2004). Since the characteristic triplet of a Lévy process is a priori an infinite-dimensional object, the parametric approach is always exposed to the problem of misspecification, in particular when there is no inherent economic foundation of the parameters and they are only used to generate different shapes of possible jump distributions. In this work we propose and test a non-parametric calibration algorithm which is based on the inversion of the explicit pricing formula via Fourier transforms and a regularisation in the spectral domain.Using the Fast Fourier Transformation, the procedure is fast, easy to implement and yields good results in simulations in view of the severe ill-posedness of the underlying inverse problem

Intracellular Fibroblast Growth Factor 14: Emerging Risk Factor for Brain Disorders

The finely tuned regulation of neuronal firing relies on the integrity of ion channel macromolecular complexes. Minimal disturbances of these tightly regulated networks can lead to persistent maladaptive plasticity of brain circuitry. The intracellular fibroblast growth factor 14 (FGF14) belongs to the nexus of proteins interacting with voltage-gated Na+ (Nav) channels at the axonal initial segment. Through isoform-specific interactions with the intracellular C-terminal tail of neuronal Nav channels (Nav1.1, Nav1.2, Nav1.6), FGF14 controls channel gating, axonal targeting and phosphorylation in neurons effecting excitability. FGF14 has been also involved in synaptic transmission, plasticity and neurogenesis in the cortico-mesolimbic circuit with cognitive and affective behavioral outcomes. In translational studies, interest in FGF14 continues to rise with a growing list of associative links to diseases of the cognitive and affective domains such as neurodegeneration, depression, anxiety, addictive behaviors and recently schizophrenia, suggesting its role as a converging node in the etiology of complex brain disorders. Yet, a full understanding of FGF14 function in neurons is far from being complete and likely to involve other functions unrelated to the direct regulation of Nav channels. The goal of this Mini Review article is to provide a summary of studies on the emerging role of FGF14 in complex brain disorders