Psychiatric diseases, including schizophrenia, bipolar disorder and major depression, are projected to lead global disease burden within the next decade. Pharmacotherapy, the primary--albeit often ...ineffective--treatment method, has remained largely unchanged over the past 50 years, highlighting the need for novel target discovery and improved mechanism-based treatments. Here, we examined in wild type mice the impact of chronic, systemic treatment with Compound 60 (Cpd-60), a slow-binding, benzamide-based inhibitor of the class I histone deacetylase (HDAC) family members, HDAC1 and HDAC2, in mood-related behavioral assays responsive to clinically effective drugs. Cpd-60 treatment for one week was associated with attenuated locomotor activity following acute amphetamine challenge. Further, treated mice demonstrated decreased immobility in the forced swim test. These changes are consistent with established effects of clinical mood stabilizers and antidepressants, respectively. Whole-genome expression profiling of specific brain regions (prefrontal cortex, nucleus accumbens, hippocampus) from mice treated with Cpd-60 identified gene expression changes, including a small subset of transcripts that significantly overlapped those previously reported in lithium-treated mice. HDAC inhibition in brain was confirmed by increased histone acetylation both globally and, using chromatin immunoprecipitation, at the promoter regions of upregulated transcripts, a finding consistent with in vivo engagement of HDAC targets. In contrast, treatment with suberoylanilide hydroxamic acid (SAHA), a non-selective fast-binding, hydroxamic acid HDAC 1/2/3/6 inhibitor, was sufficient to increase histone acetylation in brain, but did not alter mood-related behaviors and had dissimilar transcriptional regulatory effects compared to Cpd-60. These results provide evidence that selective inhibition of HDAC1 and HDAC2 in brain may provide an epigenetic-based target for developing improved treatments for mood disorders and other brain disorders with altered chromatin-mediated neuroplasticity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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.
PURPOSE OF REVIEWNumerous genome-wide association studies (GWAS) of schizophrenia have been published in the past 6 years, with a number of key reports published in the last year. The studies have ...evolved in scale from small individual samples to large collaborative endeavors. This review aims to critically assess whether the results have improved as the sample size and scale of genetic association studies have grown.
RECENT FINDINGSGenomic genotyping and increasing sample sizes for schizophrenia association studies have led to parallel increases in the number of risk genes discovered with high statistical confidence. Nearly 20 genes or loci have surpassed the genome-wide significance threshold (P = 5 × 10) in a single study, and several have been replicated in more than one GWAS.
SUMMARYIdentifying the genetic underpinnings of complex diseases offers insight into the etiological mechanisms leading to manifestation of the disease. New and more effective treatments for schizophrenia are desperately needed, and the ability to target the relevant biological processes grows with our understanding of the genes involved. As the size of GWAS samples has increased, more genes have been identified with high confidence that have begun to provide insight into the etiological and pathophysiological foundations of this disorder.
The study of individuals at clinical high risk (CHR) for psychosis provides an important opportunity for unraveling pathological mechanisms underlying schizophrenia and related disorders. A small ...number of diffusion tensor magnetic resonance imaging (DTI) studies in CHR samples have yielded anatomically inconsistent results. The present study is the first to apply tract-based spatial statistics (TBSS) to perform a whole-brain DTI analysis in CHR subjects.
A total of 28 individuals meeting CHR criteria and 34 healthy controls underwent DTI. TBSS was used for a group comparison of fractional anisotropy (FA), as well as axial, radial, and mean diffusivity (AD, RD, and MD). Conversion to psychosis was monitored during a mean follow-up period of 12.3 months.
The rate of conversion to psychosis was relatively low (4%). TBSS revealed increased MD in several clusters in the right hemisphere, most notably in the superior longitudinal fasciculus (SLF), posterior corona radiata, and corpus callosum (splenium and body). Increased RD was restricted to a smaller area in the posterior parietal lobe.
We present further evidence that white matter microstructure is abnormal in CHR individuals, even in a sample in which the vast majority do not transition to psychosis over the following year. In accord with previous studies on CHR individuals and patients with early-onset schizophrenia, our findings suggest an important pathological role for the parietal lobe and especially the SLF. The latter is known to undergo particularly dynamic microstructural changes during adolescence and early adulthood, a critical phase for the development of psychotic illness.
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 GSK3β 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 GSK3β and cAMP pathways could be beneficial in BD.
Bipolar disorder (BP) is a debilitating psychiatric disorder, affecting ∼2% of the worldwide population, for which the etiological basis, pathogenesis, and neurocircuitry remain poorly understood. ...Individuals with BP suffer from recurrent episodes of mania and depression, which are commonly treated with the mood stabilizer lithium. However, nearly half of BP patients do not respond adequately to lithium therapy and the clinically relevant mechanisms of lithium for mood stabilization remain elusive. Here, we modeled lithium responsiveness using cellular assays of glycogen synthase kinase 3 (GSK-3) signaling and mood-related behavioral assays in inbred strains of mice that differ in their response to lithium. We found that activating AKT through phosphosrylation of a key regulatory site (Thr308) was associated with lithium response-activation of signaling pathways downstream of GSK-3 in cells and attenuation of mood-related behaviors in mice-and this response was attenuated by selective and direct inhibition of AKT kinase activity. Conversely, the expression of constitutively active AKT1 in both the cellular and behavioral assays conferred lithium sensitivity. In contrast, selective and direct GSK-3 inhibition by the ATP-competitive inhibitor CHIR99021 bypassed the requirement for AKT activation and modulated behavior in both lithium-responsive and non-responsive mouse strains. These results distinguish the mechanism of action of lithium from direct GSK-3 inhibition both in vivo and in vitro, and highlight the therapeutic potential for selective GSK-3 inhibitors in BP treatment.
•Low dose ketamine (3mg/kg) or scopolamine (0.1mg/kg) is ineffective in the mouse FST.•Co-treatment with subeffective doses of both drugs has an antidepressant-like effect.•Low dose ketamine and ...scopolamine co-treatment may be effective for human depression.
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.
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