Identification of a Core Amino Acid Motif within the α Subunit of GABAARs that Promotes Inhibitory Synaptogenesis and Resilience to Seizures

The fidelity of inhibitory neurotransmission is dependent on the accumulation of γ-aminobutyric acid type A receptors (GABAARs) at the appropriate synaptic sites. Synaptic GABAARs are constructed from α(1-3), β(1-3), and γ2 subunits, and neurons can target these subtypes to specific synapses. Here, we identify a 15-amino acid inhibitory synapse targeting motif (ISTM) within the α2 subunit that promotes the association between GABAARs and the inhibitory scaffold proteins collybistin and gephyrin. Using mice in which the ISTM has been introduced into the α1 subunit (Gabra1-2 mice), we show that the ISTM is critical for axo-axonic synapse formation, the efficacy of GABAergic neurotransmission, and seizure sensitivity. The Gabra1-2 mutation rescues seizure-induced lethality in Gabra2-1 mice, which lack axo-axonic synapses due to the deletion of the ISTM from the α2 subunit. Taken together, our data demonstrate that the ISTM plays a critical role in promoting inhibitory synapse formation, both in the axonic and somatodendritic compartments

Interplay disorder-interaction in one dimensional quantum models

URL: http://www-spht.cea.fr/articles/S98/116 Compétition entre le désordre et les interactions dans des modèles quantiques unidimensionnels 210th WE-Heraeus Seminar (PILS'98), Berlin, Germany, October 6-9, 1998We show that the crossover from the weak interaction limit towards the strong interaction limit may be accompanied by a delocalization effect in one dimensional disordered quantum models. The spin degrees of freedom are frozen and the spatial wave functions remain symmetric or antisymmetric when the strength $U$ of a short range interaction is varied. The study concerns the excited states for two interacting particles and the ground state for a finite density of carriers. First, for two particles in a chain of length $L$, we establish a duality transformation mapping the behavior at weak $U$ onto the behavior at strong $U$. For intermediate $U$, the mixing of the one body states and the interaction induced delocalization effect are maximum. Furthermore, if $L \approx L_1$ (the one particle localization length), the system becomes weakly chaotic with critical spectral statistics. This weak chaos is related to the multifractality of the interaction matrix. For two particles starting close to each other, localization is reached in two steps. Before the time $t_1$ necessary to propagate over $L_1$, $U$ de-favors the propagation. On the contrary, $U$ favors a very slow delocalization after $t_1$, characterized by a $\log(t)$ spreading of the center of mass. Similarly, the curvatures of the energy levels with respect to an enclosed magnetic flux decrease as a function of $U$ for $LL_1$. The changes of the curvatures can be described by a conductance-like single scaling parameter. Second, using the density renormalization group algorithm, we have studied the ground state energy of a finite density of spinless fermions and its change under twisted boundary conditions. For a large disorder, a charge reorganization is induced by the interaction: When the system becomes instable between the inhomogeneous configuration driven by the random potential (Anderson insulator) and the homogeneous one driven by repulsive interactions (Mott insulator), the ground state sensitivity can be enhanced by orders of magnitude. In contrast, no enhancement occurs at weaker disorder, when there are many particles on a scale $L_1$. ----- Cet article est une revue des résultats obtenus récemment par les auteurs sur le rôle joué par l'interaction dans des systèmes unidimensionnels désordonnés. La première partie de l'article traite le problème de deux particules en interaction dans un potentiel aléatoire. On montre que les deux particules peuvent se propager de façon cohérente sur une distance $L_2$ beaucoup plus grande que la longueur de localisation $L_1$ d'une particule sans interaction. L'effet de délocalisation maximale se manifeste pour une valeur de l'interaction $U$ intermédiaire entre les deux limites $U=0$ et $U\to\infty$ et une transformation de dualité permet de passer d'une limite à l'autre. La structure multifractale des termes d'interaction de l'hamiltonien dans la base des états sans interaction influence la relation entre $L_2$ et $L_1$ et empêche la transition, engendrée par l'interaction, à un régime complètement chaotique. En changeant $U$ on parvient à un régime de ``chaos faible'', caractérisé par une statistique spectrale critique intermédiaire entre la statistique de Poisson (systèmes intégrables) et de Wigner (systèmes ergodiques). On montre que l'interaction est favorable au transport quand la longueur de localisation $L_1$ est plus petite que la taille $L$ du système et au contraire est défavorable quand $L_1>L$. Ceci est montré dans l'étude de la dynamique d'une paire de particules et de la courbure des niveaux énergétiques pour une boucle traversée par un flux d'Aharonov--Bohm. La deuxième partie de l'article étudie les propriétés de l'état fondamental d'un système de fermions sans spin. Des effets importants de délocalisation se manifestent quand le système devient instable entre les configurations limites $U=0$ (isolant d'Anderson) et $U\to\infty$ (isolant de Mott). La réorganisation des charges d'une limite à l'autre s'accompagne d'une grande sensibilité de l'énergie de l'état fondamental quand les conditions de bord de périodiques deviennent antipériodiques. L'article montre que l'effet de délocalisation semble persister à la limite thermodynamique. \hfill{G. Benenti

Ordered and periodic chaos of the bounded one dimensinal multibarrier potential

Numerical analysis indicates that there exists an unexpected new ordered chaos for the bounded one-dimensional multibarrier potential. For certain values of the number of barriers, repeated identical forms (periods) of the wavepackets result upon passing through the multibarrier potential.Comment: 16 pages, 9 figures, 1 Table. Some former text removed and other introduce

Discrete charging of metallic grains: Statistics of addition spectra

We analyze the statistics of electrostatic energies (and their differences) for a quantum dot system composed of a finite number $K$ of electron islands (metallic grains) with random capacitance-inductance matrix $C$, for which the total charge is discrete, $Q=Ne$ (where $e$ is the charge of an electron and $N$ is an integer). The analysis is based on a generalized charging model, where the electrons are distributed among the grains such that the electrostatic energy E(N) is minimal. Its second difference (inverse compressibility) $\chi_{N}=E(N+1)-2 E(N)+E(N-1)$ represents the spacing between adjacent Coulomb blockade peaks appearing when the conductance of the quantum dot is plotted against gate voltage. The statistics of this quantity has been the focus of experimental and theoretical investigations during the last two decades. We provide an algorithm for calculating the distribution function corresponding to $\chi_{N}$ and show that this function is piecewise polynomial.Comment: 21 pages, no figures, mathematical nomenclature (except for Abstract and Introduction

On Renyi entropies characterizing the shape and the extension of the phase space representation of quantum wave functions in disordered systems

We discuss some properties of the generalized entropies, called Renyi entropies and their application to the case of continuous distributions. In particular it is shown that these measures of complexity can be divergent, however, their differences are free from these divergences thus enabling them to be good candidates for the description of the extension and the shape of continuous distributions. We apply this formalism to the projection of wave functions onto the coherent state basis, i.e. to the Husimi representation. We also show how the localization properties of the Husimi distribution on average can be reconstructed from its marginal distributions that are calculated in position and momentum space in the case when the phase space has no structure, i.e. no classical limit can be defined. Numerical simulations on a one dimensional disordered system corroborate our expectations.Comment: 8 pages with 2 embedded eps figures, RevTex4, AmsMath included, submitted to PR

Cytoplasmic Relocalization of TAR DNA-Binding Protein 43 Is Not Sufficient to Reproduce Cellular Pathologies Associated with ALS In vitro

Mutations in the gene TARDBP, which encodes TAR DNA-binding protein 43 (TDP-43), are a rare cause of familial forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While the majority of mutations are found in the C-terminal glycine-rich domain, an alanine to valine amino acid change at position 90 (A90V) in the bipartite nuclear localization signal (NLS) of TDP-43 has been described. This sequence variant has previously been shown to cause cytoplasmic mislocalization of TDP-43 and decrease protein solubility, leading to the formation of insoluble aggregates. Since the A90V mutation has been described both in patients as well as healthy controls, its pathogenic potential in ALS and FTD remains unclear. Here we compare properties of overexpressed A90V to the highly pathogenic M337V mutation. Though both mutations drive mislocalization of the protein to the cytoplasm to the same extent, M337V produces more significant damage in terms of protein solubility, levels of pathogenic phosphorylation, and formation of C-terminal truncated protein species. Furthermore, the M337V, but not the A90V mutant, leads to a downregulation of histone deacetylase 6 and Ras GTPase-activating protein-binding protein. We conclude that in the absence of another genetic or environmental ‘hit’ the A90V variant is not sufficient to cause the deleterious phenotypes associated with ALS and FTD, despite prominent cytoplasmic protein relocalization of TDP-43

Functional investigation of the coronary artery disease gene SVEP1

A missense variant of the sushi, von Willebrand factor type A, EGF and pentraxin domain containing protein 1 (SVEP1) is genome-wide significantly associated with coronary artery disease. The mechanisms how SVEP1 impacts atherosclerosis are not known. We found endothelial cells (EC) and vascular smooth muscle cells to represent the major cellular source of SVEP1 in plaques. Plaques were larger in atherosclerosis-prone Svep1 haploinsufficient (ApoE^{−/−}Svep1^{+/−}) compared to Svep1 wild-type mice (ApoE^{−/−}Svep1^{+/+}) and ApoE^{−/−}Svep1^{+/−} mice displayed elevated plaque neutrophil, Ly6C^{high} monocyte, and macrophage numbers. We assessed how leukocytes accumulated more inside plaques in ApoE^{−/−}Svep1^{+/−} mice and found enhanced leukocyte recruitment from blood into plaques. In vitro, we examined how SVEP1 deficiency promotes leukocyte recruitment and found elevated expression of the leukocyte attractant chemokine (C-X-C motif) ligand 1 (CXCL1) in EC after incubation with missense compared to wild-type SVEP1. Increasing wild-type SVEP1 levels silenced endothelial CXCL1 release. In line, plasma Cxcl1 levels were elevated in ApoE^{−/−}Svep1^{+/−} mice. Our studies reveal an atheroprotective role of SVEP1. Deficiency of wild-type Svep1 increased endothelial CXCL1 expression leading to enhanced recruitment of proinflammatory leukocytes from blood to plaque. Consequently, elevated vascular inflammation resulted in enhanced plaque progression in Svep1 deficiency

The green tea polyphenol (-)-epigallocatechin gallate prevents the aggregation of tau protein into toxic oligomers at substoichiometric ratios

The accumulation of amyloid-beta (Abeta) and tau aggregates is a pathological hallmark of Alzheimer's disease. Both polypeptides form fibrillar deposits, but several lines of evidence indicate that Abeta and tau form toxic oligomeric aggregation intermediates. Depleting such structures could thus be a powerful therapeutic strategy. We generated a fragment of tau (His-K18DeltaK280) that forms stable, toxic, oligomeric tau aggregates in vitro. We show that (-)-epigallocatechin gallate (EGCG), a green tea polyphenol that was previously found to reduce Abeta aggregation, inhibits the aggregation of tau K18DeltaK280 into toxic oligomers at ten- to hundred-fold substoichiometric concentrations, thereby rescuing toxicity in neuronal model cells

Association of the coronary artery disease risk gene GUCY1A3 with ischaemic events after coronary intervention

Aim: A common genetic variant at the GUCY1A3 coronary artery disease locus has been shown to influence platelet aggregation. The risk of ischaemic events including stent thrombosis varies with the efficacy of aspirin to inhibit platelet reactivity. This study sought to investigate whether homozygous GUCY1A3 (rs7692387) risk allele carriers display higher on-aspirin platelet reactivity and risk of ischaemic events early after coronary intervention. Methods and results: The association of GUCY1A3 genotype and on-aspirin platelet reactivity was analysed in the genetics substudy of the ISAR-ASPI registry (n = 1678) using impedance aggregometry. The clinical outcome cardiovascular death or stent thrombosis within 30 days after stenting was investigated in a meta-analysis of substudies of the ISAR-ASPI registry, the PLATO trial (n = 3236), and the Utrecht Coronary Biobank (n = 1003) comprising a total 5917 patients. Homozygous GUCY1A3 risk allele carriers (GG) displayed increased on-aspirin platelet reactivity compared with non-risk allele (AA/AG) carriers [150 (interquartile range 91–209) vs. 134 (85–194) AU⋅min, P 203 AU⋅min; 29.5 vs. 24.2%, P = 0.02). Homozygous risk allele carriers were also at higher risk for cardiovascular death or stent thrombosis (hazard ratio 1.70, 95% confidence interval 1.08–2.68; P = 0.02). Bleeding risk was not altered. Conclusion: We conclude that homozygous GUCY1A3 risk allele carriers are at increased risk of cardiovascular death or stent thrombosis within 30 days after coronary stenting, likely due to higher on-aspirin platelet reactivity. Whether GUCY1A3 genotype helps to tailor antiplatelet treatment remains to be investigated