Synaptic Wnt/GSK3β Signaling Hub in Autism

Indexación: ScopusHundreds of genes have been associated with autism spectrum disorders (ASDs) and the interaction of weak and de novo variants derive from distinct autistic phenotypes thus making up the "spectrum." The convergence of these variants in networks of genes associated with synaptic function warrants the study of cell signaling pathways involved in the regulation of the synapse. The Wnt/β-catenin signaling pathway plays a central role in the development and regulation of the central nervous system and several genes belonging to the cascade have been genetically associated with ASDs. In the present paper, we review basic information regarding the role of Wnt/β-catenin signaling in excitatory/inhibitory balance (E/I balance) through the regulation of pre-and postsynaptic compartments. Furthermore, we integrate information supporting the role of the glycogen synthase kinase 3β (GSK3β) in the onset/development of ASDs through direct modulation of Wnt/β-catenin signaling. Finally, given GSK3β activity as key modulator of synaptic plasticity, we explore the potential of this kinase as a therapeutic target for ASD.https://www.hindawi.com/journals/np/2016/9603751

Wnt/β-catenin signaling stimulates the expression and synaptic clustering of the autism-associated Neuroligin 3 gene

Indexación: Scopus.Synaptic abnormalities have been described in individuals with autism spectrum disorders (ASD). The cell-adhesion molecule Neuroligin-3 (Nlgn3) has an essential role in the function and maturation of synapses and NLGN3 ASD-associated mutations disrupt hippocampal and cortical function. Here we show that Wnt/β-catenin signaling increases Nlgn3 mRNA and protein levels in HT22 mouse hippocampal cells and primary cultures of rat hippocampal neurons. We characterized the activity of mouse and rat Nlgn3 promoter constructs containing conserved putative T-cell factor/lymphoid enhancing factor (TCF/LEF)-binding elements (TBE) and found that their activity is significantly augmented in Wnt/β-catenin cell reporter assays. Chromatin immunoprecipitation (ChIP) assays and site-directed mutagenesis experiments revealed that endogenous β-catenin binds to novel TBE consensus sequences in the Nlgn3 promoter. Moreover, activation of the signaling cascade increased Nlgn3 clustering and co-localization with the scaffold PSD-95 protein in dendritic processes of primary neurons. Our results directly link Wnt/β-catenin signaling to the transcription of the Nlgn3 gene and support a functional role for the signaling pathway in the dysregulation of excitatory/inhibitory neuronal activity, as is observed in animal models of ASD.https://www.nature.com/articles/s41398-018-0093-y.pd

The Algebra of Physical Observables in Nonlinearly Realized Gauge Theories

We classify the physical observables in spontaneously broken nonlinearly realized gauge theories in the recently proposed loopwise expansion governed by the Weak Power-Counting (WPC) and the Local Functional Equation. The latter controls the non-trivial quantum deformation of the classical nonlinearly realized gauge symmetry, to all orders in the loop expansion. The Batalin-Vilkovisky (BV) formalism is used. We show that the dependence of the vertex functional on the Goldstone fields is obtained via a canonical transformation w.r.t. the BV bracket associated with the BRST symmetry of the model. We also compare the WPC with strict power-counting renormalizability in linearly realized gauge theories. In the case of the electroweak group we find that the tree-level Weinberg relation still holds if power-counting renormalizability is weakened to the WPC condition.Comment: 20 pages, 1 figur

X-boson cumulant approach to the periodic Anderson model

The Periodic Anderson Model (PAM) can be studied in the infinite U limit by employing the Hubbard X operators to project out the unwanted states. We have already studied this problem employing the cumulant expansion with the hybridization as perturbation, but the probability conservation of the local states (completeness) is not usually satisfied when partial expansions like the Chain Approximation (CHA) are employed. Here we treat the problem by a technique inspired in the mean field approximation of Coleman's slave-bosons method, and we obtain a description that avoids the unwanted phase transition that appears in the mean-field slave-boson method both when the chemical potential is greater than the localized level Ef at low temperatures (T) and for all parameters at intermediate T.Comment: Submited to Physical Review B 14 pages, 17 eps figures inserted in the tex

Fano resonance in electronic transport through a quantum wire with a side-coupled quantum dot: X-boson treatment

The transport through a quantum wire with a side coupled quantum dot is studied. We use the X-boson treatment for the Anderson single impurity model in the limit of $U=\infty$. The conductance presents a minimum for values of T=0 in the crossover from mixed-valence to Kondo regime due to a destructive interference between the ballistic channel associated with the quantum wire and the quantum dot channel. We obtain the experimentally studied Fano behavior of the resonance. The conductance as a function of temperature exhibits a logarithmic and universal behavior, that agrees with recent experimental results.Comment: 6 pages, 10 eps figs., revtex

Interaction between Kondo impurities in a quantum corral

We calculate the spectral densities for two impurities inside an elliptical quantum corral using exact diagonalization in the relevant Hilbert subspace and embedding into the rest of the system. For one impurity, the space and energy dependence of the change in differential conductance $\Delta = dI/dV$ observed in the quantum mirage experiment is reproduced. In presence of another impurity, $\Delta = dI/dV$ is very sensitive to the hybridization between impurity and bulk. The impurities are correlated ferromagnetically between them. A hopping $\gtrsim 0.15$ eV between impurities destroy the Kondo resonance.Comment: 4 pages, 4 figure

Influence of normal and radial contributions of local current density on local electrochemical impedance spectroscopy.

A new tri-electrode probe is presented and applied to local electrochemical impedance spectroscopy (LEIS) measurements. As opposed to two-probe systems, the three-probe one allows measurement not only of normal, but also of radial contributions of local current densities to the local impedance values. The results concerning the cases of the blocking electrode and the electrode with faradaic reaction are discussed from the theoretical point of view for a disk electrode. Numerical simulations and experimental results are compared for the case of the ferri/ferrocyanide electrode reaction at the Pt working electrode disk. At the centre of the disk, the impedance taking into account both normal and radial contributions was in good agreement with the local impedance measured in terms of only the normal contribution. At the periphery of the electrode, the impedance taking into account both normal and radial contributions differed significantly from the local impedance measured in terms of only the normal contribution. The radial impedance results at the periphery of the electrode are in good agreement with the usual explanation that the associated larger current density is attributed to the geometry of the electrode, which exhibits a greater accessibility at the electrode edge

The arctic curve of the domain-wall six-vertex model

The problem of the form of the `arctic' curve of the six-vertex model with domain wall boundary conditions in its disordered regime is addressed. It is well-known that in the scaling limit the model exhibits phase-separation, with regions of order and disorder sharply separated by a smooth curve, called the arctic curve. To find this curve, we study a multiple integral representation for the emptiness formation probability, a correlation function devised to detect spatial transition from order to disorder. We conjecture that the arctic curve, for arbitrary choice of the vertex weights, can be characterized by the condition of condensation of almost all roots of the corresponding saddle-point equations at the same, known, value. In explicit calculations we restrict to the disordered regime for which we have been able to compute the scaling limit of certain generating function entering the saddle-point equations. The arctic curve is obtained in parametric form and appears to be a non-algebraic curve in general; it turns into an algebraic one in the so-called root-of-unity cases. The arctic curve is also discussed in application to the limit shape of $q$-enumerated (with $0<q\leq 4$) large alternating sign matrices. In particular, as $q\to 0$ the limit shape tends to a nontrivial limiting curve, given by a relatively simple equation.Comment: 39 pages, 2 figures; minor correction

Enhanced Clearance of Neurotoxic Misfolded Proteins by the Natural Compound Berberine and Its Derivatives

Background: Accumulation of misfolded proteins is a common hallmark of several neurodegenerative disorders (NDs) which results from a failure or an impairment of the proteinquality control (PQC) system. The PQC system is composed by chaperones and the degradative systems (proteasome and autophagy). Mutant proteins that misfold are potentially neurotoxic, thus strategies aimed at preventing their aggregation or at enhancing their clearance are emerging as interesting therapeutic targets for NDs. Methods: We tested the natural alkaloid berberine (BBR) and some derivatives for their capability to enhance misfolded protein clearance in cell models of NDs, evaluating which degradative pathway mediates their action. Results: We found that both BBR and its semisynthetic derivatives promote degradation of mutant androgen receptor (ARpolyQ) causative of spinal and bulbar muscular atrophy, acting mainly via proteasome and preventing ARpolyQ aggregation. Overlapping effects were observed on other misfolded proteins causative of amyotrophic lateral sclerosis, frontotemporal-lobar degeneration or Huntington disease, but with selective and specific action against each different mutant protein. Conclusions: BBR and its analogues induce the clearance of misfolded proteins responsible for NDs, representing potential therapeutic tools to counteract these fatal disorders

Airy processes and variational problems

We review the Airy processes; their formulation and how they are conjectured to govern the large time, large distance spatial fluctuations of one dimensional random growth models. We also describe formulas which express the probabilities that they lie below a given curve as Fredholm determinants of certain boundary value operators, and the several applications of these formulas to variational problems involving Airy processes that arise in physical problems, as well as to their local behaviour.Comment: Minor corrections. 41 pages, 4 figures. To appear as chapter in "PASI Proceedings: Topics in percolative and disordered systems