Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling.

The Disrupted in Schizophrenia 1 (DISC1) gene is disrupted by a balanced chromosomal translocation (1; 11) (q42; q14.3) in a Scottish family with a high incidence of major depression, schizophrenia, and bipolar disorder. Subsequent studies provided indications that DISC1 plays a role in brain development. Here, we demonstrate that suppression of DISC1 expression reduces neural progenitor proliferation, leading to premature cell cycle exit and differentiation. Several lines of evidence suggest that DISC1 mediates this function by regulating GSK3beta. First, DISC1 inhibits GSK3beta activity through direct physical interaction, which reduces beta-catenin phosphorylation and stabilizes beta-catenin. Importantly, expression of stabilized beta-catenin overrides the impairment of progenitor proliferation caused by DISC1 loss of function. Furthermore, GSK3 inhibitors normalize progenitor proliferation and behavioral defects caused by DISC1 loss of function. Together, these results implicate DISC1 in GSK3beta/beta-catenin signaling pathways and provide a framework for understanding how alterations in this pathway may contribute to the etiology of psychiatric disorders.

A comparison of neurocognition and functioning in first episode psychosis populations: do research samples reflect the real world?

PURPOSE: The current study evaluates the demographic, clinical, and neurocognitive characteristics of a recruited FEP research sample, a research control group, and a FEP clinic sample that were assessed and treated within the same center and time period. METHODS: This study utilized data collected through an observational study and a retrospective chart review. Samples were ascertained in the Longitudinal Assessment and Monitoring of Clinical Status and Brain Function in Adolescents and Adults study and the Prevention and Recovery in Early Psychosis clinic. FEP clinic patients (n = 77), FEP research participants (n = 44), and age-matched controls (n = 38) were assessed using the MATRICS consensus cognitive battery and global functioning social and role scales. Between-group differences were assessed via one-way ANOVA and Chi-square analyses. RESULTS: No significant differences were observed between groups with regard to age and gender. The FEP research sample had a higher proportion of white participants, better social and role functioning, and better neurocognitive performance when compared with the FEP clinical population. The clinic sample also had more diagnostic variability and higher prevalence of substance use disorders relative to the FEP research sample. CONCLUSIONS: Researchers should be aware of how study design and recruitment practices may impact the representativeness of samples, with particular concern for equal representation of racial minorities and patients with more severe illness. Studies should be designed to minimize burden to promote a wider range of participation.

Molecular profiles of pyramidal neurons in the superior temporal cortex in schizophrenia.

Disrupted synchronized oscillatory firing of pyramidal neuronal networks in the cerebral cortex in the gamma frequency band (i.e., 30-100 Hz) mediates many of the cognitive deficits and symptoms of schizophrenia. In fact, the density of dendritic spines and the average somal area of pyramidal neurons in layer 3 of the cerebral cortex, which mediate both long-range (associational) and local (intrinsic) corticocortical connections, are decreased in subjects with this illness. To explore the molecular pathophysiology of pyramidal neuronal dysfunction, we extracted ribonucleic acid (RNA) from laser-captured pyramidal neurons from layer 3 of Brodmann's area 42 of the superior temporal gyrus (STG) from postmortem brains from schizophrenia and normal control subjects. We then profiled the messenger RNA (mRNA) expression of these neurons, using microarray technology. We identified 1331 mRNAs that were differentially expressed in schizophrenia, including genes that belong to the transforming growth factor beta (TGF-ß) and the bone morphogenetic proteins (BMPs) signaling pathways. Disturbances of these signaling mechanisms may in part contribute to the altered expression of other genes found to be differentially expressed in this study, such as those that regulate extracellular matrix (ECM), apoptosis, and cytoskeletal and synaptic plasticity. In addition, we identified 10 microRNAs (miRNAs) that were differentially expressed in schizophrenia; enrichment analysis of their predicted gene targets revealed signaling pathways and gene networks that were found by microarray to be dysregulated, raising an interesting possibility that dysfunction of pyramidal neurons in schizophrenia may in part be mediated by a concerted dysregulation of gene network functions as a result of the altered expression of a relatively small number of miRNAs. Taken together, findings of this study provide a neurobiological framework within which specific hypotheses about the molecular mechanisms of pyramidal cell dysfunction in schizophrenia can be formulated.

Excessive extracellular volume reveals a neurodegenerative pattern in schizophrenia onset.

Diffusion MRI has been successful in identifying the existence of white matter abnormalities in schizophrenia in vivo. However, the role of these abnormalities in the etiology of schizophrenia is not well understood. Accumulating evidence from imaging, histological, genetic, and immunochemical studies support the involvement of axonal degeneration and neuroinflammation--ubiquitous components of neurodegenerative disorders--as the underlying pathologies of these abnormalities. Nevertheless, the current imaging modalities cannot distinguish neuroinflammation from axonal degeneration, and therefore provide little specificity with respect to the pathophysiology progression and whether it is related to a neurodegenerative process. Free-water imaging is a new methodology that is sensitive to water molecules diffusing in the extracellular space. Excessive extracellular volume is a surrogate biomarker for neuroinflammation and can be separated out to reveal abnormalities such as axonal degeneration that affect diffusion characteristics in the tissue. We applied free-water imaging on diffusion MRI data acquired from schizophrenia-diagnosed human subjects with a first psychotic episode. We found a significant increase in the extracellular volume in both white and gray matter. In contrast, significant signs of axonal degeneration were limited to focal areas in the frontal lobe white matter. Our findings demonstrate that neuroinflammation is more prominent than axonal degeneration in the early stage of schizophrenia, revealing a pattern shared by many neurodegenerative disorders, in which prolonged inflammation leads to axonal degeneration. These findings promote anti-inflammatory treatment for early diagnosed schizophrenia patients.

Assessing the impact of population stratification on genetic association studies.

Population stratification refers to differences in allele frequencies between cases and controls due to systematic differences in ancestry rather than association of genes with disease. It has been proposed that false positive associations due to stratification can be controlled by genotyping a few dozen unlinked genetic markers. To assess stratification empirically, we analyzed data from 11 case-control and case-cohort association studies. We did not detect statistically significant evidence for stratification but did observe that assessments based on a few dozen markers lack power to rule out moderate levels of stratification that could cause false positive associations in studies designed to detect modest genetic risk factors. After increasing the number of markers and samples in a case-cohort study (the design most immune to stratification), we found that stratification was in fact present. Our results suggest that modest amounts of stratification can exist even in well designed studies.

Sex differences in the genetic risk for schizophrenia: history of the evidence for sex-specific and sex-dependent effects.

Although there is a long history to examinations of sex differences in the familial (and specifically, genetic) transmission of schizophrenia, there have been few investigators who have systematically and rigorously studied this issue. This is true even in light of population and clinical studies identifying significant sex differences in incidence, expression, neuroanatomic and functional brain abnormalities, and course of schizophrenia. This review highlights the history of work in this arena from studies of family transmission patterns, linkage and twin studies to the current molecular genetic strategies of large genome-wide association studies. Taken as a whole, the evidence supports the presence of genetic risks of which some are sex-specific (i.e., presence in one sex and not the other) or sex-dependent (i.e., quantitative differences in risk between the sexes). Thus, a concerted effort to systematically investigate these questions is warranted and, as we argue here, necessary in order to fully understand the etiology of schizophrenia.

Lithium rescues dendritic abnormalities in Ank3 deficiency models through the synergic effects of GSK3ß and cyclic AMP signaling pathways.

Bipolar disorder (BD) is a highly heritable mood disorder with intermittent episodes of mania and depression. Lithium is the first-in-line medication to treat BD, but it is only effective in a subset of individuals. Large-scale human genomic studies have repeatedly linked the ANK3 gene (encoding ankyrin-G, AnkG) to BD. Ank3 knockout mouse models mimic BD behavioral features and respond positively to lithium treatment. We investigated cellular phenotypes associated with BD, including dendritic arborization of pyramidal neurons and spine morphology in two models: (1) a conditional knockout mouse model which disrupts Ank3 expression in adult forebrain pyramidal neurons, and (2) an AnkG knockdown model in cortical neuron cultures. We observed a decrease in dendrite complexity and a reduction of dendritic spine number in both models, reminiscent of reports in BD. We showed that lithium treatment corrected dendrite and spine deficits in vitro and in vivo. We targeted two signaling pathways known to be affected by lithium using a highly selective GSK3ß inhibitor (CHIR99021) and an adenylate cyclase activator (forskolin). In our cortical neuron culture model, CHIR99021 rescues the spine morphology defects caused by AnkG knockdown, whereas forskolin rescued the dendrite complexity deficit. Interestingly, a synergistic action of both drugs was required to rescue dendrite and spine density defects in AnkG knockdown neurons. Altogether, our results suggest that dendritic abnormalities observed in loss of function ANK3 variants and BD patients may be rescued by lithium treatment. Additionally, drugs selectively targeting GSK3ß and cAMP pathways could be beneficial in BD.

Genome-wide analyses of smoking behaviors in schizophrenia: Findings from the Psychiatric Genomics Consortium.

While 17% of US adults use tobacco regularly, smoking rates among persons with schizophrenia are upwards of 60%. Research supports a shared etiological basis for smoking and schizophrenia, including findings from genome-wide association studies (GWAS). However, few studies have directly tested whether the same or distinct genetic variants also influence smoking behavior among schizophrenia cases. Using data from the Psychiatric Genomics Consortium (PGC) study of schizophrenia (35476 cases, 46839 controls), we estimated genetic correlations between these traits and tested whether polygenic risk scores (PRS) constructed from the results of smoking behaviors GWAS were associated with schizophrenia risk or smoking behaviors among schizophrenia cases. Results indicated significant genetic correlations of schizophrenia with smoking initiation (rg = 0.159; P = 5.05 × 10-10), cigarettes-smoked-per-day (rg = 0.094; P = 0.006), and age-of-onset of smoking (rg = 0.10; P = 0.009). Comparing smoking behaviors among schizophrenia cases to the general population, we observe positive genetic correlations for smoking initiation (rg = 0.624, P = 0.002) and cigarettes-smoked-per-day (rg = 0.689, P = 0.120). Similarly, TAG-based PRS for smoking initiation and cigarettes-smoked-per-day were significantly associated with smoking initiation (P = 3.49 × 10-5) and cigarettes-smoked-per-day (P = 0.007) among schizophrenia cases. We performed the first GWAS of smoking behavior among schizophrenia cases and identified a novel association with cigarettes-smoked-per-day upstream of the TMEM106B gene on chromosome 7p21.3 (rs148253479, P = 3.18 × 10-8, n = 3520). Results provide evidence of a partially shared genetic basis for schizophrenia and smoking behaviors. Additionally, genetic risk factors for smoking behaviors were largely shared across schizophrenia and non-schizophrenia populations. Future research should address mechanisms underlying these associations to aid both schizophrenia and smoking treatment and prevention efforts.

Examining Sex-Differentiated Genetic Effects Across Neuropsychiatric and Behavioral Traits.

BACKGROUND: The origin of sex differences in prevalence and presentation of neuropsychiatric and behavioral traits is largely unknown. Given established genetic contributions and correlations, we tested for a sex-differentiated genetic architecture within and between traits. METHODS: Using European ancestry genome-wide association summary statistics for 20 neuropsychiatric and behavioral traits, we tested for sex differences in single nucleotide polymorphism (SNP)-based heritability and genetic correlation (rg < 1). For each trait, we computed per-SNP z scores from sex-stratified regression coefficients and identified genes with sex-differentiated effects using a gene-based approach. We calculated correlation coefficients between z scores to test for shared sex-differentiated effects. Finally, we tested for sex differences in across-trait genetic correlations. RESULTS: We observed no consistent sex differences in SNP-based heritability. Between-sex, within-trait genetic correlations were high, although <1 for educational attainment and risk-taking behavior. We identified 4 genes with significant sex-differentiated effects across 3 traits. Several trait pairs shared sex-differentiated effects. The top genes with sex-differentiated effects were enriched for multiple gene sets, including neuron- and synapse-related sets. Most between-trait genetic correlation estimates were not significantly different between sexes, with exceptions (educational attainment and risk-taking behavior). CONCLUSIONS: Sex differences in the common autosomal genetic architecture of neuropsychiatric and behavioral phenotypes are small and polygenic and unlikely to fully account for observed sex-differentiated attributes. Larger sample sizes are needed to identify sex-differentiated effects for most traits. For well-powered studies, we identified genes with sex-differentiated effects that were enriched for neuron-related and other biological functions. This work motivates further investigation of genetic and environmental influences on sex differences.

The Relationship Between Polygenic Risk Scores and Cognition in Schizophrenia.

BACKGROUND: Cognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases. METHODS: We combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognition and PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognition was conducted in schizophrenia cases. RESULTS: PRS for both population IQ (P = 4.39 × 10-28) and EA (P = 1.27 × 10-26) were positively correlated with cognition in those with schizophrenia. In contrast, there was no association between cognition in schizophrenia cases and PRS for schizophrenia (P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS. CONCLUSIONS: Cognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself. Our findings indicate that this cognitive variation arises at least in part due to genetic factors shared with cognitive performance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors.

The genetics of reading disability.

Genetic factors contribute substantially to the development of reading disability (RD). Family linkage studies have implicated many chromosomal regions containing RD susceptibility genes, of which putative loci at 1p34-p36 (DYX8), 2p (DYX3), 6p21.3 (DYX2), and 15q21 (DYX1) have been frequently replicated, whereas those at 3p12-q12 (DYX5), 6q13-q16 (DYX4), 11p15 (DYX7), 18p11 (DYX6), and Xq27 (DYX9) have less evidence. Association studies of positional candidate genes have implicated DCDC2 and KIAA0319 in DYX2, as well as C2ORF3 and MRPL19 (DYX3), whereas DYX1C1/EKN1 (DYX1) and ROBO1 (DYX5) were found to be disrupted by rare translocation breakpoints in reading-disabled individuals. Four of the candidate genes (DYX1C1, KIAA0319, DCDC2, and ROBO1) appear to function in neuronal migration and guidance, suggesting the importance of early neurodevelopmental processes in RD. Future studies to help us understand the function of these and other RD candidate genes promise to yield enormous insight into the neurobiologic mechanisms underlying the pathophysiology of this disorder.

Disruption of the psychiatric risk gene Ankyrin 3 enhances microtubule dynamics through GSK3/CRMP2 signaling.

The ankyrin 3 gene (ANK3) is a well-established risk gene for psychiatric illness, but the mechanisms underlying its pathophysiology remain elusive. We examined the molecular effects of disrupting brain-specific Ank3 isoforms in mouse and neuronal model systems. RNA sequencing of hippocampus from Ank3+/- and Ank3+/+ mice identified altered expression of 282 genes that were enriched for microtubule-related functions. Results were supported by increased expression of microtubule end-binding protein 3 (EB3), an indicator of microtubule dynamics, in Ank3+/- mouse hippocampus. Live-cell imaging of EB3 movement in primary neurons from Ank3+/- mice revealed impaired elongation of microtubules. Using a CRISPR-dCas9-KRAB transcriptional repressor in mouse neuro-2a cells, we determined that repression of brain-specific Ank3 increased EB3 expression, decreased tubulin acetylation, and increased the soluble:polymerized tubulin ratio, indicating enhanced microtubule dynamics. These changes were rescued by inhibition of glycogen synthase kinase 3 (GSK3) with lithium or CHIR99021, a highly selective GSK3 inhibitor. Brain-specific Ank3 repression in neuro-2a cells increased GSK3 activity (reduced inhibitory phosphorylation) and elevated collapsin response mediator protein 2 (CRMP2) phosphorylation, a known GSK3 substrate and microtubule-binding protein. Pharmacological inhibition of CRMP2 activity attenuated the rescue of EB3 expression and tubulin polymerization in Ank3-repressed cells by lithium or CHIR99021, suggesting microtubule instability induced by Ank3 repression is dependent on CRMP2 activity. Taken together, our data indicate that ANK3 functions in neuronal microtubule dynamics through GSK3 and its downstream substrate CRMP2. These findings reveal cellular and molecular mechanisms underlying brain-specific ANK3 disruption that may be related to its role in psychiatric illness.

Abnormal relationships between local and global brain measures in subjects at clinical high risk for psychosis: a pilot study.

We examined whether abnormal volumes of several brain regions as well as their mutual associations that have been observed in patients with schizophrenia, are also present in individuals at clinical high-risk (CHR) for developing psychosis. 3T magnetic resonance imaging was acquired in 19 CHR and 20 age- and handedness-matched controls. Volumes were measured for the body and temporal horns of the lateral ventricles, hippocampus and amygdala as well as total brain, cortical gray matter, white matter, and subcortical gray matter volumes. Relationships between volumes as well as correlations between volumes and cognitive and clinical measures were explored. Ratios of lateral ventricular volume to total brain volume and temporal horn volume to total brain volume were calculated. Volumetric abnormalities were lateralized to the left hemisphere. Volumes of the left temporal horn, and marginally, of the body of the left lateral ventricle were larger, while left amygdala but not hippocampal volume was significantly smaller in CHR participants compared to controls. Total brain volume was also significantly smaller and the ratio of the temporal horn/total brain volume was significantly higher in CHR than in controls. White matter volume correlated positively with higher verbal fluency score while temporal horn volume correlated positively with a greater number of perseverative errors. Together with the finding of larger temporal horns and smaller amygdala volumes in the left hemisphere, these results indicate that the ratio of temporal horns volume to brain volume is abnormal in CHR compared to controls. These abnormalities present in CHR individuals may constitute the biological basis for at least some of the CHR syndrome.

Alteration of gray matter microstructure in schizophrenia.

Neuroimaging studies demonstrate gray matter (GM) macrostructural abnormalities in patients with schizophrenia (SCZ). While ex-vivo and genetic studies suggest cellular pathology associated with abnormal neurodevelopmental processes in SCZ, few in-vivo measures have been proposed to target microstructural GM organization. Here, we use diffusion heterogeneity- to study GM microstructure in SCZ. Structural and diffusion magnetic resonance imaging (MRI) were acquired on a 3 Tesla scanner in 46 patients with SCZ and 37 matched healthy controls (HC). After correction for free water, diffusion heterogeneity as well as commonly used diffusion measures FA and MD and volume were calculated for the four cortical lobes on each hemisphere, and compared between groups. Patients with early course SCZ exhibited higher diffusion heterogeneity in the GM of the frontal lobes compared to controls. Diffusion heterogeneity of the frontal lobe showed excellent discrimination between patients and HC, while none of the commonly used diffusion measures such as FA or MD did. Higher diffusion heterogeneity in the frontal lobes in early SCZ may be due to abnormal brain maturation (migration, pruning) before and during adolescence and early adulthood. Further studies are needed to investigate the role of heterogeneity as potential biomarker for SCZ risk.

Lithium reverses behavioral and axonal transport-related changes associated with ANK3 bipolar disorder gene disruption.

Ankyrin 3 (ANK3) has been implicated as a genetic risk factor for bipolar disorder (BD), however the resulting pathophysiological and treatment implications remain elusive. In a preclinical systems biological approach, we aimed to characterize the behavioral and proteomic effects of Ank3 haploinsufficiency and chronic mood-stabilizer treatment in mice. Psychiatric-related behavior was evaluated with the novelty-suppressed feeding (NSF) paradigm, elevated plus maze (EPM) and a passive avoidance task (PAT). Tandem mass spectrometry (MSE) was employed for hippocampal proteome profiling. A functional enrichment approach based on protein-protein interactions (PPIs) was performed to outline which biological processes in the hippocampus were affected by Ank3 haploinsufficiency and lithium treatment. Proteomic abundance changes as detected by MSE or highlighted by PPI network modelling were followed up by targeted selected reaction monitoring (SRM). Increased psychiatric-related behavior in Ank3+/- mice was ameliorated by lithium in all assessments (NSF, EPM, PAT). MSE followed by modular PPI clustering and functional annotation enrichment pointed towards kinesin-related axonal transport and glutamate signaling as mediators of Ank3+/- pathophysiology and lithium treatment. SRM validated this hypothesis and further confirmed abundance changes of ANK3 interaction partners. We propose that psychiatric-related behavior in Ank3+/- mice is connected to a disturbance of the kinesin cargo system, resulting in a dysfunction of neuronal ion channel and glutamate receptor transport. Lithium reverses this molecular signature, suggesting the promotion of anterograde kinesin transport as part of its mechanism of action in ameliorating Ank3-related psychiatric-related behavior.

Heritability of Neuropsychological Measures in Schizophrenia and Nonpsychiatric Populations: A Systematic Review and Meta-analysis.

Schizophrenia is characterized by neuropsychological deficits across many cognitive domains. Cognitive phenotypes with high heritability and genetic overlap with schizophrenia liability can help elucidate the mechanisms leading from genes to psychopathology. We performed a meta-analysis of 170 published twin and family heritability studies of >800 000 nonpsychiatric and schizophrenia subjects to accurately estimate heritability across many neuropsychological tests and cognitive domains. The proportion of total variance of each phenotype due to additive genetic effects (A), shared environment (C), and unshared environment and error (E), was calculated by averaging A, C, and E estimates across studies and weighting by sample size. Heritability ranged across phenotypes, likely due to differences in genetic and environmental effects, with the highest heritability for General Cognitive Ability (32%-67%), Verbal Ability (43%-72%), Visuospatial Ability (20%-80%), and Attention/Processing Speed (28%-74%), while the lowest heritability was observed for Executive Function (20%-40%). These results confirm that many cognitive phenotypes are under strong genetic influences. Heritability estimates were comparable in nonpsychiatric and schizophrenia samples, suggesting that environmental factors and illness-related moderators (eg, medication) do not substantially decrease heritability in schizophrenia samples, and that genetic studies in schizophrenia samples are informative for elucidating the genetic basis of cognitive deficits. Substantial genetic overlap between cognitive phenotypes and schizophrenia liability (average rg = -.58) in twin studies supports partially shared genetic etiology. It will be important to conduct comparative studies in well-powered samples to determine whether the same or different genes and genetic variants influence cognition in schizophrenia patients and the general population.

Novel gene-brain structure relationships in psychotic disorder revealed using parallel independent component analyses.

BACKGROUND: Schizophrenia, schizoaffective disorder, and psychotic bipolar disorder overlap with regard to symptoms, structural and functional brain abnormalities, and genetic risk factors. Neurobiological pathways connecting genes to clinical phenotypes across the spectrum from schizophrenia to psychotic bipolar disorder remain largely unknown. METHODS: We examined the relationship between structural brain changes and risk alleles across the psychosis spectrum in the multi-site Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) cohort. Regional MRI brain volumes were examined in 389 subjects with a psychotic disorder (139 schizophrenia, 90 schizoaffective disorder, and 160 psychotic bipolar disorder) and 123 healthy controls. 451,701 single-nucleotide polymorphisms were screened and processed using parallel independent component analysis (para-ICA) to assess associations between genes and structural brain abnormalities in probands. RESULTS: 482 subjects were included after quality control (364 individuals with psychotic disorder and 118 healthy controls). Para-ICA identified four genetic components including several risk genes already known to contribute to schizophrenia and bipolar disorder and revealed three structural components that showed overlapping relationships with the disease risk genes across the three psychotic disorders. Functional ontologies representing these gene clusters included physiological pathways involved in brain development, synaptic transmission, and ion channel activity. CONCLUSIONS: Heritable brain structural findings such as reduced cortical thickness and surface area in probands across the psychosis spectrum were associated with somewhat distinct genes related to putative disease pathways implicated in psychotic disorders. This suggests that brain structural alterations might represent discrete psychosis intermediate phenotypes along common neurobiological pathways underlying disease expression across the psychosis spectrum.

Two quantitative trait loci for prepulse inhibition of startle identified on mouse chromosome 16 using chromosome substitution strains.

Prepulse inhibition (PPI) of acoustic startle is a genetically complex quantitative phenotype of considerable medical interest due to its impairment in psychiatric disorders such as schizophrenia. To identify quantitative trait loci (QTL) involved in mouse PPI, we studied mouse chromosome substitution strains (CSS) that each carry a homologous chromosome pair from the A/J inbred strain on a host C57BL/6J inbred strain background. We determined that the chromosome 16 substitution strain has elevated PPI compared to C57BL/6J (P = 1.6 x 10(-11)), indicating that chromosome 16 carries one or more PPI genes. QTL mapping using 87 F(2) intercross progeny identified two significant chromosome 16 loci with LODs of 3.9 and 4.7 (significance threshold LOD is 2.3). The QTL were each highly significant independently and do not appear to interact. Sequence variation between B6 and A/J was used to identify strong candidate genes in the QTL regions, some of which have known neuronal functions. In conclusion, we used mouse CSS to rapidly and efficiently identify two significant QTL for PPI on mouse chromosome 16. The regions contain a limited number of strong biological candidate genes that are potential risk genes for psychiatric disorders in which patients have PPI impairments.

Antidepressant-like effect of low dose ketamine and scopolamine co-treatment in mice.

Current medications for depression typically require weeks of treatment before significant clinical improvement is observed, and are only effective in a relatively small subset of patients. Recent human clinical studies have demonstrated that ketamine, an NMDA receptor antagonist, and scopolamine, a muscarinic acetylcholine receptor antagonist, produce rapid antidepressant responses within hours of administration, and are effective in treatment-resistant patients. We hypothesize that efficacy and tolerability may be improved by combining lower doses of both drugs in the treatment of depression. We therefore conducted a preclinical study in mice to assess whether co-treatment of low doses of scopolamine and ketamine that alone are ineffective has antidepressant-like effects in the forced swim test (FST), an assay with predictive validity for antidepressant drugs. Whereas single administration of ketamine (3mg/kg intraperitoneal [i.p.]) or scopolamine (0.1mg/kg i.p.) did not reduce immobility time in the FST, co-administration of both drugs at these doses significantly reduced immobility time by 45% compared to vehicle treated controls. These results suggest that the combination of subeffective doses of ketamine and scopolamine may prove efficacious for the treatment of depression and should be evaluated in human clinical trials.

A New MRI Masking Technique Based on Multi-Atlas Brain Segmentation in Controls and Schizophrenia: A Rapid and Viable Alternative to Manual Masking.

UNLABELLED: Brain masking of MRI images separates brain from surrounding tissue and its accuracy is important for further imaging analyses. We implemented a new brain masking technique based on multi-atlas brain segmentation (MABS) and compared MABS to masks generated using FreeSurfer (FS; version 5.3), Brain Extraction Tool (BET), and Brainwash, using manually defined masks (MM) as the gold standard. We further determined the effect of different masking techniques on cortical and subcortical volumes generated by FreeSurfer. METHODS: Images were acquired on a 3-Tesla MR Echospeed system General Electric scanner on five control and five schizophrenia subjects matched on age, sex, and IQ. Automated masks were generated from MABS, FS, BET, and Brainwash, and compared to MM using these metrics: a) volume difference from MM; b) Dice coefficients; and c) intraclass correlation coefficients. RESULTS: Mean volume difference between MM and MABS masks was significantly less than the difference between MM and FS or BET masks. Dice coefficient between MM and MABS was significantly higher than Dice coefficients between MM and FS, BET, or Brainwash. For subcortical and left cortical regions, MABS volumes were closer to MM volumes than were BET or FS volumes. For right cortical regions, MABS volumes were closer to MM volumes than were BET volumes. CONCLUSIONS: Brain masks generated using FreeSurfer, BET, and Brainwash are rapidly obtained, but are less accurate than manually defined masks. Masks generated using MABS, in contrast, resemble more closely the gold standard of manual masking, thereby offering a rapid and viable alternative.