Insulin-like growth factor 2 (IGF-2) rescues social deficits in NLG3–/y mouse model of ASDs

Autism spectrum disorders (ASDs) comprise developmental disabilities characterized by impairments of social interaction and repetitive behavior, often associated with cognitive deficits. There is no current treatment that can ameliorate most of the ASDs symptomatology; thus, identifying novel therapies is urgently needed. Here, we used the Neuroligin 3 knockout mouse (NLG3–/y), a model that recapitulates the social deficits reported in ASDs patients, to test the effects of systemic administration of IGF-2, a polypeptide that crosses the blood-brain barrier and acts as a cognitive enhancer. We show that systemic IGF-2 treatment reverses the typical defects in social interaction and social novelty discrimination reflective of ASDs-like phenotypes. This effect was not accompanied by any change in spontaneous glutamatergic synaptic transmission in CA2 hippocampal region, a mechanism found to be crucial for social novelty discrimination. However, in both NLG3+/y and NLG3–/y mice IGF-2 increased cell excitability. Although further investigation is needed to clarify the cellular and molecular mechanisms underpinning IGF-2 effect on social behavior, our findings highlight IGF-2 as a potential pharmacological tool for the treatment of social dysfunctions associated with ASDs

Pin1-dependent signaling negatively affects GABAergic transmission by modulating neuroligin2/gephyrin interaction

The cell adhesion molecule Neuroligin2 (NL2) is localized selectively at GABAergic synapses, where it interacts with the scaffolding protein gephyrin in the post-synaptic density. However, the role of this interaction for formation and plasticity of GABAergic synapses is unclear. Here, we demonstrate that endogenous NL2 undergoes proline-directed phosphorylation at its unique S714-P consensus site, leading to the recruitment of the peptidyl-prolyl cis-trans isomerase Pin1. This signalling cascade negatively regulates NL2' s ability to interact with gephyrin at GABAergic post-synaptic sites. As a consequence, enhanced accumulation of NL2, gephyrin and GABA A receptors was detected at GABAergic synapses in the hippocampus of Pin1-knockout mice (Pin1\ufffd/\ufffd) associated with an increase in amplitude of spontaneous GABA A -mediated post-synaptic currents. Our results suggest that Pin1-dependent signalling represents a mechanism to modulate GABAergic transmission by regulating NL2/gephyrin interaction. \ufffd 2014 Macmillan Publishers Limited. All rights reserved

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

In hippocampal oriens interneurons anti-Hebbian Long-Term Potentiation requires cholinergic signalling via alpha 7 nicotinic acetylcholine receptors

In the hippocampus, at excitatory synapses between principal cell and oriens/alveus (O/A) interneurons, a particular form of NMDAindependent long-term synaptic plasticity (LTP) has been described (Lamsa et al., 2007). This type of LTP occurs when presynaptic activation coincides with postsynaptic hyperpolarization. For this reason it has been named "anti-Hebbian" to distinguish from the classical Hebbian type of associative learning where presynaptic glutamate release coincides with postsynaptic depolarization. The different voltage dependency of LTP induction is thought to be mediated by calcium-permeable (CP) AMPA receptors that, due to polyamine-mediated rectification, favor calcium entry at hyperpolarized potentials. Here, we report that the induction of this form of LTP needs CP-\u3b17 nicotinic acetylcholine receptors (nAChRs) that, like CP-AMPARs, exhibit a strong inward rectification because of polyamine block at depolarizing potentials. We found that high-frequency stimulation of afferent fibers elicits synaptic currents mediated by \u3b17 nAChRs. Hence, LTP was prevented by \u3b17 nAChR antagonists dihydro-\u3b2-erythroidine and methyllycaconitine (MLA) and was absent in \u3b17 -/- mice. In addition, in agreement with previous observations (Le Duigou and Kullmann, 2011), in a minority of O/A interneuronsin MLA-treated hippocampal slices from WT animals and \u3b17 -/- mice, a form of LTP probably dependent on the activation of group I metabotropic glutamate receptors was observed. These data indicate that, in O/A interneurons, anti-Hebbian LTP critically depends on cholinergic signaling via \u3b17 nAChR. This may influence network oscillations and information processing. \ua9 2013 the authors

Study of a backgated metal‐semiconductor‐metal photodetector

In this letter we outline our results on a new type of high-speed photodetector [E. Gregor , Appl. Phys. Lett. 65, 2223 (1994)]. The device is based on the hybridization of a metal-semiconductor-metal photodetector and a p-i-n photodiode. The advantage of the device, which operates in the transit-time limited regime, is that it removes the hole current from the high-speed circuit through a third contact, and hence, increases the response speed of the device. In contrast to the previously published work [E. Gregor , Appl. Phys. Lett. 65, 2223 (1994)] we have used an excitation pulse that is much faster than the device response in order to fully investigate the effect of the third contact. We observe significantly more effect on the response once the third contact is connected with a subsequent increase of device response speed with increasing application of bias to this third contact. © 1996 American Institute of Physics