Inhibition of STEP61 ameliorates deficits in mouse and hiPSC-based schizophrenia models.

The brain-specific tyrosine phosphatase, STEP (STriatal-Enriched protein tyrosine Phosphatase) is an important regulator of synaptic function. STEP normally opposes synaptic strengthening by increasing N-methyl D-aspartate glutamate receptor (NMDAR) internalization through dephosphorylation of GluN2B and inactivation of the kinases extracellular signal-regulated kinase 1/2 and Fyn. Here we show that STEP61 is elevated in the cortex in the Nrg1+/- knockout mouse model of schizophrenia (SZ). Genetic reduction or pharmacological inhibition of STEP prevents the loss of NMDARs from synaptic membranes and reverses behavioral deficits in Nrg1+/- mice. STEP61 protein is also increased in cortical lysates from the central nervous system-specific ErbB2/4 mouse model of SZ, as well as in human induced pluripotent stem cell (hiPSC)-derived forebrain neurons and Ngn2-induced excitatory neurons, from two independent SZ patient cohorts. In these selected SZ models, increased STEP61 protein levels likely reflect reduced ubiquitination and degradation. These convergent findings from mouse and hiPSC SZ models provide evidence for STEP61 dysfunction in SZ.

Common polygenic variation and risk for childhood-onset schizophrenia.

Childhood-onset schizophrenia (COS) is a rare and severe form of the disorder, with more striking abnormalities with respect to prepsychotic developmental disorders and abnormities in the brain development compared with later-onset schizophrenia. We previously documented that COS patients, compared with their healthy siblings and with adult-onset patients (AOS), carry significantly more rare chromosomal copy number variations, spanning large genomic regions (>100 kb) (Ahn et al. 2014). Here, we interrogated the contribution of common polygenic variation to the genetic susceptibility for schizophrenia. We examined the association between a direct measure of genetic risk of schizophrenia in 130 COS probands and 103 healthy siblings. Using data from the schizophrenia and autism GWAS of the Psychiatric Genomic Consortia, we selected three risk-related sets of single nucleotide polymorphisms from which we conducted polygenic risk score comparisons for COS probands and their healthy siblings. COS probands had higher genetic risk scores of both schizophrenia and autism than their siblings (P<0.05). Given the small sample size, these findings suggest that COS patients have more salient genetic risk than do AOS.

Subcortical and cortical morphological anomalies as an endophenotype in obsessive-compulsive disorder.

Endophentoypes, quantifiable traits lying on the causal chain between a clinical phenotype and etiology, can be used to accelerate genomic discovery in obsessive-compulsive disorder (OCD). Here we identify the neuroanatomic changes that are shared by 22 OCD adult and adolescent patients and 25 of their unaffected siblings who are at genetic risk for the disorder. Comparisons were made against 47 age and sex matched healthy controls. We defined the surface morphology of the striatum, globus pallidus and thalamus, and thickness of the cerebral cortex. Patients with OCD show significant surface expansion compared with healthy controls, following adjustment for multiple comparisons, in interconnected regions of the caudate, thalamus and right orbitofrontal cortex. Their unaffected siblings show similar, significant expansion, most marked in the ventromedial caudate bilaterally, the right pulvinar thalamic nucleus and the right orbitofrontal cortex. These regions define a network that has been consistently implicated in OCD. In addition, both patients with OCD and unaffected siblings showed similar increased thickness of the right precuneus, which receives rich input from the thalamic pulvinar nuclei and the left medial temporal cortex. Anatomic change within the orbitofrontostriatal and posterior brain circuitry thus emerges as a promising endophenotype for OCD.

Hippocampal volume change relates to clinical outcome in childhood-onset schizophrenia.

BACKGROUND: Fixed hippocampal volume reductions and shape abnormalities are established findings in schizophrenia, but the relationship between hippocampal volume change and clinical outcome has been relatively unexplored in schizophrenia and other psychotic disorders. In light of recent findings correlating hippocampal volume change and clinical outcome in first-episode psychotic adults, we hypothesized that fewer decreases in hippocampal volume would be associated with better functional outcome and fewer psychotic symptoms in our rare and chronically ill population of childhood-onset schizophrenia (COS) patients. METHOD: We prospectively obtained 114 structural brain magnetic resonance images (MRIs) from 27 COS subjects, each with three or more scans between the ages of 10 and 30 years. Change in hippocampal volume, measured by fit slope and percentage change, was regressed against clinical ratings (Children's Global Assessment Scale, Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms) at last scan (controlling for sex, time between scans and total intracranial volume). RESULTS: Fewer negative symptoms were associated with less hippocampal volume decrease (fit slope: p = 0.0003, and percentage change: p = 0.005) while positive symptoms were not related to hippocampal change. There was also a relationship between improved clinical global functioning and maintained hippocampal volumes (fit slope: p = 0.025, and percentage change: p = 0.043). CONCLUSIONS: These results suggest that abnormal hippocampal development in schizophrenia can be linked to global functioning and negative symptoms. The hippocampus can be considered a potential treatment target for future therapies.

High rate of disease-related copy number variations in childhood onset schizophrenia.

Copy number variants (CNVs) are risk factors in neurodevelopmental disorders, including autism, epilepsy, intellectual disability (ID) and schizophrenia. Childhood onset schizophrenia (COS), defined as onset before the age of 13 years, is a rare and severe form of the disorder, with more striking array of prepsychotic developmental disorders and abnormalities in brain development. Because of the well-known phenotypic variability associated with pathogenic CNVs, we conducted whole genome genotyping to detect CNVs and then focused on a group of 46 rare CNVs that had well-documented risk for adult onset schizophrenia (AOS), autism, epilepsy and/or ID. We evaluated 126 COS probands, 69 of which also had a healthy full sibling. When COS probands were compared with their matched related controls, significantly more affected individuals carried disease-related CNVs (P=0.017). Moreover, COS probands showed a higher rate than that found in AOS probands (P<0.0001). A total of 15 (11.9%) subjects exhibited at least one such CNV and four of these subjects (26.7%) had two. Five of 15 (4.0% of the sample) had a 2.5-3 Mb deletion mapping to 22q11.2, a rate higher than that reported for adult onset (0.3-1%) (P<0.001) or autism spectrum disorder and, indeed, the highest rate reported for any clinical population to date. For one COS subject, a duplication found at 22q13.3 had previously only been associated with autism, and for four patients CNVs at 8q11.2, 10q22.3, 16p11.2 and 17q21.3 had only previously been associated with ID. Taken together, these findings support the well-known pleiotropic effects of these CNVs suggesting shared abnormalities early in brain development. Clinically, broad CNV-based population screening is needed to assess their overall clinical burden.

Neurodevelopmental model of schizophrenia: update 2012.

The neurodevelopmental model of schizophrenia, which posits that the illness is the end state of abnormal neurodevelopmental processes that started years before the illness onset, is widely accepted, and has long been dominant for childhood-onset neuropsychiatric disorders. This selective review updates our 2005 review of recent studies that have impacted, or have the greatest potential to modify or extend, the neurodevelopmental model of schizophrenia. Longitudinal whole-population studies support a dimensional, rather than categorical, concept of psychosis. New studies suggest that placental pathology could be a key measure in future prenatal high-risk studies. Both common and rare genetic variants have proved surprisingly diagnostically nonspecific, and copy number variants (CNVs) associated with schizophrenia are often also associated with autism, epilepsy and intellectual deficiency. Large post-mortem gene expression studies and prospective developmental multi-modal brain imaging studies are providing critical data for future clinical and high-risk developmental brain studies. Whether there can be greater molecular specificity for phenotypic characterization is a subject of current intense study and debate, as is the possibility of neuronal phenotyping using human pluripotent-inducible stem cells. Biological nonspecificity, such as in timing or nature of early brain development, carries the possibility of new targets for broad preventive treatments.

Transcriptome profiling of UPF3B/NMD-deficient lymphoblastoid cells from patients with various forms of intellectual disability.

The nonsense-mediated mRNA decay (NMD) pathway was originally discovered by virtue of its ability to rapidly degrade aberrant mRNAs with premature termination codons. More recently, it was shown that NMD also directly regulates subsets of normal transcripts, suggesting that NMD has roles in normal biological processes. Indeed, several NMD factors have been shown to regulate neurological events (for example, neurogenesis and synaptic plasticity) in numerous vertebrate species. In man, mutations in the NMD factor gene UPF3B, which disrupts a branch of the NMD pathway, cause various forms of intellectual disability (ID). Using Epstein Barr virus-immortalized B cells, also known as lymphoblastoid cell lines (LCLs), from ID patients that have loss-of-function mutations in UPF3B, we investigated the genome-wide consequences of compromised NMD and the role of NMD in neuronal development and function. We found that ~5% of the human transcriptome is impacted in UPF3B patients. The UPF3B paralog, UPF3A, is stabilized in all UPF3B patients, and partially compensates for the loss of UPF3B function. Interestingly, UPF3A protein, but not mRNA, was stabilised in a quantitative manner that inversely correlated with the severity of patients' phenotype. This suggested that the ability to stabilize the UPF3A protein is a crucial modifier of the neurological symptoms due to loss of UPF3B. We also identified ARHGAP24, which encodes a GTPase-activating protein, as a canonical target of NMD, and we provide evidence that deregulation of this gene inhibits axon and dendrite outgrowth and branching. Our results demonstrate that the UPF3B-dependent NMD pathway is a major regulator of the transcriptome and that its targets have important roles in neuronal cells.

Parental age effects on cortical morphology in offspring.

The age at which a parent has a child impacts the child's cognition and risk for mental illness. It appears that this risk is curvilinear, with both age extremes associated with lower intelligence and increased prevalence of some neuropsychiatric disorders. Little is known of the neural mechanisms underpinning this phenomenon. We extracted lobar volumes, surface areas, and cortical thickness from 489 neuroanatomic magnetic resonance images acquired on 171 youth. Using linear mixed model regression, we determined the association between parental age and offspring's neuroanatomy, adjusting for offspring's age, sex, intelligence, and parental socioeconomic class. For gray matter volumes, quadratic paternal and maternal age terms contributed significantly (maternal quadratic age effect: t = -2.2, P = 0.03; paternal quadratic age effect: t = -2.4, P = 0.02) delineating an inverted "U" relationship between parental age and gray matter volume. Cortical volume increased with both advancing paternal and maternal age until around the early 30s after which it fell. Paternal age effects were more pronounced on cortical surface area, whereas maternal age impacted more on cortical thickness. There were no significant effects of parental age on white matter volumes. These parental age effects on cerebral morphology may form part of the link between parental age extremes and suboptimal neurocognitive outcomes.

Common functional polymorphisms of DISC1 and cortical maturation in typically developing children and adolescents.

Disrupted-in-schizophrenia-1 (DISC1), contains two common non-synonymous single-nucleotide polymorphisms (SNPs)--Leu607Phe and Ser704Cys--that modulate (i) facets of DISC1 molecular functioning important for cortical development, (ii) fronto-temporal cortical anatomy in adults and (iii) risk for diverse psychiatric phenotypes that often emerge during childhood and adolescence, and are associated with altered fronto-temporal cortical development. It remains unknown, however, if Leu607Phe and Ser704Cys influence cortical maturation before adulthood, and whether each SNP shows unique or overlapping effects. Therefore, we related genotype at Leu607Phe and Ser704Cys to cortical thickness (CT) in 255 typically developing individuals aged 9-22 years on whom 598 magnetic resonance imaging brain scans had been acquired longitudinally. Rate of cortical thinning varied with DISC1 genotype. Specifically, the rate of cortical thinning was attenuated in Phe-carrier compared with Leu-homozygous groups (in bilateral superior frontal and left angular gyri) and accelerated in Ser-homozygous compared with Cys-carrier groups (in left anterior cingulate and temporal cortices). Both SNPs additively predicted fixed differences in right lateral temporal CT, which were maximal between Phe-carrier/Ser-homozygous (thinnest) vs Leu-homozygous/Cys-carrier (thickest) groups. Leu607Phe and Ser704Cys genotype interacted to predict the rate of cortical thinning in right orbitofrontal, middle temporal and superior parietal cortices, wherein a significantly reduced rate of CT loss was observed in Phe-carrier/Cys-carrier participants only. Our findings argue for further examination of Leu607Phe and Ser704Cys interactions at a molecular level, and suggest that these SNPs might operate (in concert with other genetic and environmental factors) to shape risk for diverse phenotypes by impacting on the early maturation of fronto-temporal cortices.

Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia.

Autism spectrum disorder (ASD) and schizophrenia (SCZ) are two common neurodevelopmental syndromes that result from the combined effects of environmental and genetic factors. We set out to test the hypothesis that rare variants in many different genes, including de novo variants, could predispose to these conditions in a fraction of cases. In addition, for both disorders, males are either more significantly or more severely affected than females, which may be explained in part by X-linked genetic factors. Therefore, we directly sequenced 111 X-linked synaptic genes in individuals with ASD (n = 142; 122 males and 20 females) or SCZ (n = 143; 95 males and 48 females). We identified >200 non-synonymous variants, with an excess of rare damaging variants, which suggest the presence of disease-causing mutations. Truncating mutations in genes encoding the calcium-related protein IL1RAPL1 (already described in Piton et al. Hum Mol Genet 2008) and the monoamine degradation enzyme monoamine oxidase B were found in ASD and SCZ, respectively. Moreover, several promising non-synonymous rare variants were identified in genes encoding proteins involved in regulation of neurite outgrowth and other various synaptic functions (MECP2, TM4SF2/TSPAN7, PPP1R3F, PSMD10, MCF2, SLITRK2, GPRASP2, and OPHN1).

Intellectual ability and cortical development in children and adolescents.

Children who are adept at any one of the three academic 'R's (reading, writing and arithmetic) tend to be good at the others, and grow into adults who are similarly skilled at diverse intellectually demanding activities. Determining the neuroanatomical correlates of this relatively stable individual trait of general intelligence has proved difficult, particularly in the rapidly developing brains of children and adolescents. Here we demonstrate that the trajectory of change in the thickness of the cerebral cortex, rather than cortical thickness itself, is most closely related to level of intelligence. Using a longitudinal design, we find a marked developmental shift from a predominantly negative correlation between intelligence and cortical thickness in early childhood to a positive correlation in late childhood and beyond. Additionally, level of intelligence is associated with the trajectory of cortical development, primarily in frontal regions implicated in the maturation of intelligent activity. More intelligent children demonstrate a particularly plastic cortex, with an initial accelerated and prolonged phase of cortical increase, which yields to equally vigorous cortical thinning by early adolescence. This study indicates that the neuroanatomical expression of intelligence in children is dynamic.

Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation.

There is controversy over the nature of the disturbance in brain development that underpins attention-deficit/hyperactivity disorder (ADHD). In particular, it is unclear whether the disorder results from a delay in brain maturation or whether it represents a complete deviation from the template of typical development. Using computational neuroanatomic techniques, we estimated cortical thickness at >40,000 cerebral points from 824 magnetic resonance scans acquired prospectively on 223 children with ADHD and 223 typically developing controls. With this sample size, we could define the growth trajectory of each cortical point, delineating a phase of childhood increase followed by adolescent decrease in cortical thickness (a quadratic growth model). From these trajectories, the age of attaining peak cortical thickness was derived and used as an index of cortical maturation. We found maturation to progress in a similar manner regionally in both children with and without ADHD, with primary sensory areas attaining peak cortical thickness before polymodal, high-order association areas. However, there was a marked delay in ADHD in attaining peak thickness throughout most of the cerebrum: the median age by which 50% of the cortical points attained peak thickness for this group was 10.5 years (SE 0.01), which was significantly later than the median age of 7.5 years (SE 0.02) for typically developing controls (log rank test chi(1)(2) = 5,609, P < 1.0 x 10(-20)). The delay was most prominent in prefrontal regions important for control of cognitive processes including attention and motor planning. Neuroanatomic documentation of a delay in regional cortical maturation in ADHD has not been previously reported.

Retention of antidiuretic hormone-induced particle aggregates by luminal membranes separated from toad bladder epithelial cells.

Aggregates of intramembrane particles appear in the luminal membranes of renal collecting duct and amphibian bladder cells after stimulation by antidiuretic hormone (ADH). We undertook this freeze-fracture study to determine whether particle aggregates, once in place, remain in the luminal membrane of the amphibian bladder after the membrane is physically separated from the rest of the cell. We found that the aggregates do remain in high yield in isolated membranes stabilized with a bifunctional imidoester (DTBP) followed by fixation with glutaraldehyde, or unfixed but stabilized with DTBP. These findings support the view that the particles are intrinsic membrane components and that their organization in the form of aggregates does not depend on the presence of the intact cell. In addition, the availability of isolated membranes containing particle aggregates provides a starting point for the isolation of the water-conducting proteins.

Stabilization of vasopressin-induced membrane events by bifunctional imidoesters.

Vasopressin increases the water permeability of the luminal membrane of the toad bladder epithelial cell. This change in permeability correlates with the occurrence in luminal membranes of intramembrane particle aggregates, which may be the sites for transmembrane water flow. Withdrawal of vasopressin is ordinarily associated with a rapid reduction of water flow to baseline values and a simultaneous disappearance of the particle aggregates. The bifunctional imidoesters dithiobispropionimidate (DTBP) and dimethylsuberimidate (DMS), which cross-link amino groups in membrane proteins and lipids, slow the return of water flow to baseline after vasopressin withdrawal. Cross-linking is maximal at pH 10, and is reduced as pH is lowered. Freeze-fracture studies show persistence of luminal membrane particle aggregates in cross-linked bladders and a reduction in their frequency as water flow diminishes. Fusion of aggregate-containing cytoplasmic tubular membrane structures with the luminal membrane is also maintained by the imidoesters. Reductive cleavage of the central S-S bond of DTBP by beta-mercaptoethanol reverses cross-linking, permitting resumption of the rapid disappearance of the vasopressin effect. Bladders that have undergone DTBP cross-linking and beta-mercaptoethanol reduction respond to a second stimulation by vasopressin. Thus, the imidoesters provide a physiologic and reversible means of stabilizing normally rapid membrane events.

Dextroamphetamine: cognitive and behavioral effects in normal prepubertal boys.

The behavioral, cognitive, and electrophysiological effect of a single dose of dextroamphetamine (0.5 milligram per kilogram of body weight) or placebo was examined in 14 normal prepubertal boys (mean age, 10 years 11 months) in a double-blind study. When amphetamine was given, the group showed a marked decrease in motor activity and reaction time and improved performance on cognitive tests. The similarity of the response observed in normal children to that reported in children with "hyperactivity" or minimal brain dysfunction casts doubt on pathophysiological models of minimal brain dysfunction which assume that children with this syndrome have a clinically specific or "paradoxical" response to stimulants.

Structural maturation of neural pathways in children and adolescents: in vivo study.

Structural maturation of fiber tracts in the human brain, including an increase in the diameter and myelination of axons, may play a role in cognitive development during childhood and adolescence. A computational analysis of structural magnetic resonance images obtained in 111 children and adolescents revealed age-related increases in white matter density in fiber tracts constituting putative corticospinal and frontotemporal pathways. The maturation of the corticospinal tract was bilateral, whereas that of the frontotemporal pathway was found predominantly in the left (speech-dominant) hemisphere. These findings provide evidence for a gradual maturation, during late childhood and adolescence, of fiber pathways presumably supporting motor and speech functions.

Gender differences in ambulatory blood pressure monitoring profile in obese, overweight and normal subjects.

The incidence of obesity has increased enormously in the past several decades, and has been described as a modern epidemic. Obesity is a major factor contributing to hypertension. To the best of our knowledge, no study of ambulatory blood pressure monitoring (ABPM) comparing men with women in relation to body mass indexes (BMI) has been performed. From December 2002 to May 2006, we performed 24-h ABPM in 5950 subjects (3102 men and 2848 women), with a wide range of BMI (range 15.9-53.2 kg/m(2)). We defined obese subjects as those with BMI> or =30.0 kg/m(2), overweight subjects as those with BMI>25.0 and <30.0 kg/m(2), and normal subjects as those with BMI< or =25.0 kg/m(2). Data on 989 subjects (501 men and 488 women) aged from > or =18 to < or =69 years without antihypertensive treatment, atrial fibrillation or diabetes were included for analysis. We consistently found that obese men had the expected increased heart rate compared to normal and overweight men, whereas women (normal, overweight and obese) had similar HRs. In addition, normal and obese women had similar diastolic blood pressures (BP), as opposed to obese men, who had raised diastolic BP. These results may indicate that different pathogenetic mechanisms may be involved in the relationship between obesity and hypertension in men and women.

Segmental uniparental isodisomy on 5q32-qter in a patient with childhood-onset schizophrenia.

Schizophrenia is a severe mental disorder affecting approximately 1% of the world's population. Although the aetiology of schizophrenia is complex and multifactorial, with estimated heritabilities as high as 80%, genetic factors are the most compelling. Childhood-onset schizophrenia (COS), defined as onset of schizophrenia before the age of 13 years, is a rare and malignant form of the illness that may have more salient genetic influence. The first known case of paternal segmental uniparental isodisomy (iUPD) on 5q32-qter in a patient with COS is described, which adds to the previously known high rates of chromosomal abnormalities reported in this sample. iUPD is a rare genetic condition in which the offspring receives two chromosomal homologues from one parent. Segmental UPD is defined as UPD on a portion of a chromosome with biparental inheritance seen in the rest of the homologous pair. Complications owing to this abnormality may arise from malfunctioning imprinted genes or homozygosity of recessive disease-causing mutations. This aberration became apparent during whole-genomic screening of a COS cohort and is of particular interest because 5q has been implicated in schizophrenia by several genomewide linkage studies and positive gene associations. This report, therefore, presents more evidence that schizophrenia susceptibility gene, or genes, may be found on distal 5q.