Diminished Perisomatic GABAergic Terminals on Cortical Neurons Adjacent to Amyloid Plaques

One of the main pathological hallmarks of Alzheimer's disease (AD) is the accumulation of plaques in the cerebral cortex, which may appear either in the neuropil or in direct association with neuronal somata. Since different axonal systems innervate the dendritic (mostly glutamatergic) and perisomatic (mostly GABAergic) regions of neurons, the accumulation of plaques in the neuropil or associated with the soma might produce different alterations to synaptic circuits. We have used a variety of conventional light, confocal and electron microscopy techniques to study their relationship with neuronal somata in the cerebral cortex from AD patients and APP/PS1 transgenic mice. The main finding was that the membrane surfaces of neurons (mainly pyramidal cells) in contact with plaques lack GABAergic perisomatic synapses. Since these perisomatic synapses are thought to exert a strong influence on the output of pyramidal cells, their loss may lead to the hyperactivity of the neurons in contact with plaques. These results suggest that plaques modify circuits in a more selective manner than previously thought

HAmsys 2014

In this talk we give an explanation of transport in the solar system based in dynamical systems theory. More concretely we consider (as a first approximation) different bicircular problems (i.e. Sun, Jupiter, a planet and an infinitesimal mass), we take sl natural periodic orbits which are unstable and we study their invariant manifolds as well as the existence of possible heteroclinic connections. The role that these particular trajectories play in relation with transport from exterior planets to the inner ones is discussed. Finally, some comments concerning a more realistic model of the Solar System are given and dynamical substitutes of invariant objects (from simpler models) are obtainedPostprint (published version

HAmsys 2014

In this talk we give an explanation of transport in the solar system based in dynamical systems theory. More concretely we consider (as a first approximation) different bicircular problems (i.e. Sun, Jupiter, a planet and an infinitesimal mass), we take sl natural periodic orbits which are unstable and we study their invariant manifolds as well as the existence of possible heteroclinic connections. The role that these particular trajectories play in relation with transport from exterior planets to the inner ones is discussed. Finally, some comments concerning a more realistic model of the Solar System are given and dynamical substitutes of invariant objects (from simpler models) are obtaine

Polygenic risk scores enhance prediction of body mass index increase in individuals with a first episode of psychosis

Background. Individuals with a first episode of psychosis (FEP) show rapid weight gain during the first months of treatment, which is associated with a reduction in general physical health. Although genetics is assumed to be a significant contributor to weight gain, its exact role is unknown. Methods. We assembled a population-based FEP cohort of 381 individuals that was split into a Training (n = 224) set and a Validation (n = 157) set to calculate the polygenic risk score (PRS) in a two-step process. In parallel, we obtained reference genome-wide association studies for body mass index (BMI) and schizophrenia (SCZ) to examine the pleiotropic landscape between the two traits. BMI PRSs were added to linear models that included sociodemographic and clinical variables to predict BMI increase (ΔBMI) in the Validation set. Results. The results confirmed considerable shared genetic susceptibility for the two traits involving 449 near-independent genomic loci. The inclusion of BMI PRSs significantly improved the prediction of ΔBMI at 12 months after the onset of antipsychotic treatment by 49.4% compared to a clinical model. In addition, we demonstrated that the PRS containing pleiotropic information between BMI and SCZ predicted ΔBMI better at 3 (12.2%) and 12 months (53.2%). Conclusions. We prove for the first time that genetic factors play a key role in determining ΔBMI during the FEP. This finding has important clinical implications for the early identifi- cation of individuals most vulnerable to weight gain and highlights the importance of examining genetic pleiotropy in the context of medically important comorbidities for predicting future outcomes

DDR1 methylation is associated with bipolar disorder and the isoform expression and methylation of myelin genes

Aim: To investigate DDR1 methylation in the brains of bipolar disorder (BD) patients and its association with DDR1 mRNA levels and comethylation with myelin genes. Materials & methods: Genome-wide profiling of DNA methylation (Infinium MethylationEPIC BeadChip) corrected for glial composition and DDR1 gene expression analysis in the occipital cortices of individuals with BD (n = 15) and healthy controls (n = 15) were conducted. Results: DDR1 5-methylcytosine levels were increased and directly associated with DDR1b mRNA expression in the brains of BD patients. We also observed that DDR1 was comethylated with a group of myelin genes. Conclusion: DDR1 is hypermethylated in BD brain tissue and is associated with isoform expression. Additionally, DDR1 comethylation with myelin genes supports the role of this receptor in myelination

Discoidin domain receptor 1 gene variants are associated with decreased white matter fractional anisotropy and decreased processing speed in schizophrenia

DDR1 has been linked to schizophrenia (SZ) and myelination. Here, we tested whether DDR1 variants in people at risk for SZ influence white matter (WM) structural variations and cognitive processing speed (PS). First, following a case-control design (Study 1), SZ patients (N = 1193) and controls (N = 1839) were genotyped for rs1264323 and rs2267641 at DDR1, and the frequencies were compared. We replicated the association between DDR1 and SZ (rs1264323, adjusted P = 0.015). Carriers of the rs1264323AA combined with the rs2267641AC or CC genotype are at risk to develop SZ compared to the other genotype combinations. Second, SZ patients (Study 2, N = 194) underwent an evaluation of PS using the Trail Making Test (TMT) and DDR1 genotyping. To compare PS between DDR1 genotype groups, we conducted an analysis of covariance (including rs1264323 as a covariate) and found that SZ patients with the rs2267641CC genotype had decreased PS compared to patients with the AA and AC genotypes. Third, 54 patients (Study 3) from Study 2 were selected based on rs1264323 genotype to undergo reevaluation, including a DTI-MRI brain scan. To test for associations between PS, WM microstructure and DDR1 genotype, we first localized those WM regions where fractional anisotropy (FA) was correlated with PS and tested whether FA showed differences between the rs1264323 genotypes. SZ patients with the rs1264323AA genotype showed decreased FA in WM regions associated with decreased PS. We conclude that DDR1 variants may confer a risk of SZ through WM microstructural alterations leading to cognitive dysfunction