Synaptic changes in cortical and subcortical brain formations in old rats

Electron microscopy was used to study structural changes of synapses in sensorimotor, parietal, limbic cortical areas, hippocamp, blue spot and hypothalamus of old Wistar rats, aged 28-30 months. Polymorphism of ultrastructural changes in neuronal and synapse processes and individual variability of these shifts in the brain of old rats have been revealed. The predominant damage of post-synaptic synapse components with ageing is demonstrated. Along with dystrophic and destructive changes in pre- and post-synaptic parts of the contact, signs of compensatory adaptive resettings in inter-neuronal links have been detected.     

Whole-genome sequencing of monozygotic twins discordant for schizophrenia indicates multiple genetic risk factors for schizophrenia

Schizophrenia is a common disorder with a high heritability, but its genetic architecture is still elusive.We implemented whole-genome sequencing(WGS) analysis of 8 families with monozygotic(MZ) twin pairs discordant for schizophrenia to assess potential association of de novo mutations(DNMs) or inherited variants with susceptibility to schizophrenia. Eight non-synonymous DNMs(including one splicing site) were identified and shared by twins, which were either located in previously reported schizophrenia risk genes(p.V24689 I mutation in TTN, p.S2506 T mutation in GCN1L1, IVS3+1G T in DOCK1) or had a benign to damaging effect according to in silico prediction analysis. By searching the inherited rare damaging or loss-of-function(LOF) variants and common susceptible alleles from three classes of schizophrenia candidate genes, we were able to distill genetic alterations in several schizophrenia risk genes, including GAD1, PLXNA2, RELN and FEZ1. Four inherited copy number variations(CNVs; including a large deletion at 16p13.11) implicated for schizophrenia were identified in four families, respectively. Most of families carried both missense DNMs and inherited risk variants, which might suggest that DNMs, inherited rare damaging variants and common risk alleles together conferred to schizophrenia susceptibility. Our results support that schizophrenia is caused by a combination of multiple genetic factors, with each DNM/variant showing a relatively small effect size.     

The role of risk subcortical brain regions in the formation alalie

Complex children examination with alalia was based the analysis by the role of subcortical brain structures for the formation of speech was investigated. Alalia is systemic speech underdevelopment in children, which violated all the components of speech. Evaluation of the functional state of brain structures on the EEG has allowed to distinguish the two groups, which depend on the nature of changes in bioelectric activity (BEA). The first group is one with the changes of alpha rhythm and/or local changes in BEA predominantly in the left hemisphere, the second group with violations ofbrainstem origin, mainly generalized EEG changes. A comprehensive analysis of clinical data has allowed to suggest the basis of the formation alalia lies subcortical structures lesion of the left hemisphere of the brain and stem departments of one. The analysis of perinatal risk factors has allowed to hypothesize about the connection of subcortical structures lesion with antenatal complications in the first half of pregnancy.     

Correction of changes induced by toluene in the cortical and subcortical structures of albino rat brain

The number and weight of cells in the cortical and subcortical structures of the cerebral and cerebellar motor system in albino rats after a long-term exposure to toluene were determined. Toluene intoxication proved to kill projection neurons and interneurons in the sensorimotor cortex, ventrolateral thalamic nucleus, caudate nucleus, pallidum, red nucleus, and inferior olivary complex. The decreased number of cerebellar cells was mediated by atrophic changes as indicated by the decrease in the area and dry weight of Purkinje cells. The addition of plaferon LB to the diet attenuated the cytotoxic effect of toluene.     

Activity of acetyl- and butyrylcholinesterase of the hemispheres and several subcortical zones of the human brain in prenatal ontogenesis

Histochemical investigations of acetyl- and butyrilcholinesterase (AChE and BChE) activity in the cortical plate and in some subcortical areas of the human brain have demonstrated that on the 8th week of the prenatal development of the greatest AChE and BChE activity is observed in the dorsal thalamus, epithalamus and in the ependymal layer of various cerebral parts, the forebrain including. The data obtained, prove previous observations, concerning predominant localization of AChE in the intermediate layer of the isocortex (10 weeks). In a 10-week-old human fetus a total high level of AChE and BChE activity is demonstrated in various nuclei of the thalamus and in subcortical structures of the forebrain (nucl. caudatus, Meynert nucl.).     

Neuropsychological effects of the CSMD1 genome‐wide associated schizophrenia risk variant rs10503253

The single‐nucleotide polymorphism (SNP) rs10503253, located within the CUB and Sushi multiple domains‐1 (CSMD1) gene on 8p23.2, was recently identified as genome‐wide significant for schizophrenia (SZ), but is of unknown function. We investigated the neurocognitive effects of this CSMD1 variant in vivo in patients and healthy participants using behavioral and imaging measures of brain structure and function. We compared carriers and non‐carriers of the risk ‘A’ allele on measures of neuropsychological performance typically impaired in SZ (general cognitive ability, episodic and working memory and attentional control) in independent samples of Irish patients (n = 387) and controls (n = 171) and German patients (205) and controls (n = 533). Across these groups, the risk ‘A’ allele at CSMD1 was associated with deleterious effects across a number of neurocognitive phenotypes. Specifically, the risk allele was associated with poorer performance on neuropsychological measures of general cognitive ability and memory function but not attentional control. These effects, while significant, were subtle, and varied between samples. Consistent with previous evidence suggesting that CSMD1 may be involved in brain mechanisms related to memory and learning, these data appear to reflect the deleterious effects of the identified ‘A’ risk allele on neurocognitive function, possibly as part of the mechanism by which CSMD1 is associated with SZ risk.     

Genetic architecture of subcortical brain regions: common and region‐specific genetic contributions

Understanding the aetiology of patterns of variation within and covariation across brain regions is key to advancing our understanding of the functional, anatomical and developmental networks of the brain. Here we applied multivariate twin modelling and principal component analysis (PCA) to investigate the genetic architecture of the size of seven subcortical regions (caudate nucleus, thalamus, putamen, pallidum, hippocampus, amygdala and nucleus accumbens) in a genetically informative sample of adolescents and young adults (N = 1038; mean age = 21.6 ± 3.2 years; including 148 monozygotic and 202 dizygotic twin pairs) from the Queensland Twin IMaging (QTIM) study. Our multivariate twin modelling identified a common genetic factor that accounts for all the heritability of intracranial volume (0.88) and a substantial proportion of the heritability of all subcortical structures, particularly those of the thalamus (0.71 out of 0.88), pallidum (0.52 out of 0.75) and putamen (0.43 out of 0.89). In addition, we also found substantial region‐specific genetic contributions to the heritability of the hippocampus (0.39 out of 0.79), caudate nucleus (0.46 out of 0.78), amygdala (0.25 out of 0.45) and nucleus accumbens (0.28 out of 0.52). This provides further insight into the extent and organization of subcortical genetic architecture, which includes developmental and general growth pathways, as well as the functional specialization and maturation trajectories that influence each subcortical region.     

Polymorphism of RGS2 gene as genetic marker of schizophrenia risk and pharmacogenetic markers of the efficiency of typical neuroleptics

Schizophrenia affects about 1% of the general population. The group of RGS genes that regulate the signaling activity of G protein and modulate signal transduction by the neurotransmitter receptors involved in the pathogenesis of schizophrenia is currently under active investigation. The association of polymorphism in the RGS2 gene with the occurrence of extrapyramidal disorders induced by neuroleptics was demonstrated previously. The present work involved the analysis of DNA from 258 patients with paranoid schizophrenia and 263 healthy blood donors resident in the Republic of Bashkortostan and belonging to Russian and Tatar ethnic groups. Genetic markers of increased risk of paranoid schizophrenia, namely, the genotype RGS2*G/*G (rs2746071) in Russians (p = 0.001, OR = 4.08) and Tatars (p = 0.000; OR = 4.88), the allele RGS2*G (rs2746071) in Russians (p = 0.00003, OR = 2.37) and Tatars (p = 0.000; OR = 2.51), as well as genetic markers associated with reduced disease risk, were identified. Moreover, genetic markers associated with increased risk of neuroleptic parkinsonism in Russian patients with paranoid schizophrenia treated with the typical antipsychotic haloperidol (RGS2*T/*T (rs2746073), RGS2*C/*C (rs4606), and RGS2*A/*A (rs2746071)) and genetic markers of efficient haloperidol therapy in Tatars were identified. The results are consistent with those obtained previously and support the hypothesis concerning the association of RGS2 gene polymorphisms with the risk of extrapyramidal syndrome development during haloperidol therapy and their involvement in the etiology and pathogenesis of schizophrenia.     

Regional brain differences in cortical thickness, surface area and subcortical volume in individuals with Williams syndrome

Williams syndrome (WS) is a rare genetic neurodevelopmental disorder characterized by increased non-social anxiety, sensitivity to sounds and hypersociability. Previous studies have reported contradictory findings with regard to regional brain variation in WS, relying on only one type of morphological measure (usually volume) in each study. The present study aims to contribute to this body of literature and perhaps elucidate some of these discrepancies by examining concurrent measures of cortical thickness, surface area and subcortical volume between WS subjects and typically-developing (TD) controls. High resolution MRI scans were obtained on 31 WS subjects and 50 typically developing control subjects. We derived quantitative regional estimates of cortical thickness, cortical surface area, and subcortical volume using FreeSurfer software. We evaluated between-group ROI differences while controlling for total intracranial volume. In post-hoc exploratory analyses within the WS group, we tested for correlations between regional brain variation and Beck Anxiety Inventory scores. Consistent with our hypothesis, we detected complex patterns of between-group cortical variation, which included lower surface area in combination with greater thickness in the following cortical regions: post central gyrus, cuneus, lateral orbitofrontal cortex and lingual gyrus. Additional cortical regions showed between-group differences in one (but not both) morphological measures. Subcortical volume was lower in the basal ganglia and the hippocampus in WS versus TD controls. Exploratory correlations revealed that anxiety scores were negatively correlated with gray matter surface area in insula, OFC, rostral middle frontal, superior temporal and lingual gyrus. Our results were consistent with previous reports showing structural alterations in regions supporting the socio-affective and visuospatial impairments in WS. However, we also were able to effectively capture novel and complex patterns of cortical differences using both surface area and thickness. In addition, correlation results implicate specific brain regions in levels of anxiety in WS, consistent with previous reports investigating general anxiety disorders in the general population.