Chemogenetics is a newly developed set of tools that allow for selective manipulation of cell activity. They consist of a receptor mutated irresponsive to endogenous ligands and a synthetic ligand that does not interact with the wild-type receptors. Many different types of these receptors and their respective ligands for inhibiting or excitating neuronal subpopulations were designed in the past few decades. It has been mainly the G-protein coupled receptors (GPCRs) selectively responding to clozapine-N-oxide (CNO), namely Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), that have been employed in research. Chemogenetics offers great possibilities since the activity of the receptors is reversible, inducible on demand by the ligand, and non-invasive. Also, specific groups or types of neurons can be selectively manipulated thanks to the delivery by viral vectors. The effect of the chemogenetic receptors on neurons lasts longer, and even chronic activation can be achieved. That can be useful for behavioral testing. The great advantage of chemogenetic tools is especially apparent in research on brain diseases since they can manipulate whole neuronal circuits and connections between different brain areas. Many psychiatric or other brain diseases revolve around the dysfunction of specific brain networks. Therefore, chemogenetics presents a powerful tool for investigating the underlying mechanisms causing the disease and revealing the link between the circuit dysfunction and the behavioral or cognitive symptoms observed in patients. It could also contribute to the development of more effective treatments.
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- duševní poruchy * genetika metabolismus MeSH
- klozapin analogy a deriváty farmakologie terapeutické užití MeSH
- lidé MeSH
- neurony metabolismus účinky léků MeSH
- nové syntetické drogy farmakologie MeSH
- receptory spřažené s G-proteiny metabolismus genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- MeSH
- celogenomová asociační studie MeSH
- duševní poruchy * genetika MeSH
- fenotyp * MeSH
- genetická predispozice k nemoci genetika MeSH
- lidé MeSH
- multifaktoriální dědičnost * genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- úvodníky MeSH
The etiopathogenesis of mental disorders is not fully understood and accumulating evidence support that clinical symptomatology cannot be assigned to a single gene mutation, but it involves several genetic factors. More specifically, a tight association between genes and environmental risk factors, which could be mediated by epigenetic mechanisms, may play a role in the development of mental disorders. Several data suggest that epigenetic modifications such as DNA methylation, post-translational histone modification and interference of microRNA (miRNA) or long non-coding RNA (lncRNA) may modify the severity of the disease and the outcome of the therapy. Indeed, the study of these mechanisms may help to identify patients particularly vulnerable to mental disorders and may have potential utility as biomarkers to facilitate diagnosis and treatment of psychiatric disorders. This article summarizes the most relevant preclinical and human data showing how epigenetic modifications can be central to the therapeutic efficacy of antidepressant and/or antipsychotic agents, as possible predictor of drugs response.
BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
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- celogenomová asociační studie MeSH
- depresivní porucha unipolární * genetika MeSH
- duševní poruchy * genetika MeSH
- jednonukleotidový polymorfismus MeSH
- lidé MeSH
- pokus o sebevraždu MeSH
- rizikové faktory MeSH
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- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Common variation in the gene encoding the neuron-specific RNA splicing factor RNA Binding Fox-1 Homolog 1 (RBFOX1) has been identified as a risk factor for several psychiatric conditions, and rare genetic variants have been found causal for autism spectrum disorder (ASD). Here, we explored the genetic landscape of RBFOX1 more deeply, integrating evidence from existing and new human studies as well as studies in Rbfox1 knockout mice. Mining existing data from large-scale studies of human common genetic variants, we confirmed gene-based and genome-wide association of RBFOX1 with risk tolerance, major depressive disorder and schizophrenia. Data on six mental disorders revealed copy number losses and gains to be more frequent in ASD cases than in controls. Consistently, RBFOX1 expression appeared decreased in post-mortem frontal and temporal cortices of individuals with ASD and prefrontal cortex of individuals with schizophrenia. Brain-functional MRI studies demonstrated that carriers of a common RBFOX1 variant, rs6500744, displayed increased neural reactivity to emotional stimuli, reduced prefrontal processing during cognitive control, and enhanced fear expression after fear conditioning, going along with increased avoidance behaviour. Investigating Rbfox1 neuron-specific knockout mice allowed us to further specify the role of this gene in behaviour. The model was characterised by pronounced hyperactivity, stereotyped behaviour, impairments in fear acquisition and extinction, reduced social interest, and lack of aggression; it provides excellent construct and face validity as an animal model of ASD. In conclusion, convergent translational evidence shows that common variants in RBFOX1 are associated with a broad spectrum of psychiatric traits and disorders, while rare genetic variation seems to expose to early-onset neurodevelopmental psychiatric disorders with and without developmental delay like ASD, in particular. Studying the pleiotropic nature of RBFOX1 can profoundly enhance our understanding of mental disorder vulnerability.
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- celogenomová asociační studie MeSH
- depresivní porucha unipolární * genetika MeSH
- duševní poruchy * genetika MeSH
- lidé MeSH
- myši knockoutované MeSH
- myši MeSH
- poruchy autistického spektra * genetika MeSH
- sestřihové faktory genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Příčiny duševních poruch jsou komplexní, podílejí se na nich faktory genetické (bodové polymorfismy DNA, variace počtu kopií v oblasti DNA, epistáze genů) i faktory zevního prostředí (biologické, psychologické, sociální, spirituální), při interakcích genů a prostředí se pak nezřídka uplatňuje epigenetika. Tento článek podává přehled hlavních obecných principů, které se uplatňují jako příčiny duševních poruch. K moderním trendům výzkumu patří například nové postupy genetického vyšetřování včetně inovativních statistických postupů zpracování jejich výsledků, objektivizace a kvantifikace vlivů zevního prostředí, vytváření nadnárodních multicentrických vědeckých konsorcií či hledání genetických a environmentálních faktorů preventivních.
Causes of mental disorders are complex. Both genetic (single nucleotide polymorphisms, copy number variations, epistasis) and environmental (biological, psychological, social, spiritual) factors participate in their etiology. Epigenetics frequently plays an important role in gene-environment interactions. This review sums up the basic knowledge on general principles in etiology of mental disorders. New DNA sequencing techniques including innovative statistical procedures, validation and quantification of environmental factors, creation of international multicentric research consortia or seeking of protective factors in etiology of mental disorders belong to recent trends.
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- duševní poruchy * etiologie genetika MeSH
- epigenomika MeSH
- genetika MeSH
- lidé MeSH
- poruchy vyvolané vnějšími činiteli MeSH
- sociální prostředí MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
- MeSH
- duševní poruchy genetika MeSH
- genetická predispozice k nemoci MeSH
- genetika * MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- biografie MeSH
- O autorovi
- Mendel, Johann Gregor, 1822-1884 Autorita
Tuberous sclerosis complex (TSC) is a dominant autosomal genetic disorder caused by loss-of-function mutations in TSC1 and TSC2, which lead to constitutive activation of the mammalian target of rapamycin C1 (mTORC1) with its decoupling from regulatory inputs. Because mTORC1 integrates an array of molecular signals controlling protein synthesis and energy metabolism, its unrestrained activation inflates cell growth and division, resulting in the development of benign tumors in the brain and other organs. In humans, brain malformations typically manifest through a range of neuropsychiatric symptoms, among which mental retardation, intellectual disabilities with signs of autism, and refractory seizures, which are the most prominent. TSC in the rat brain presents the first-rate approximation of cellular and molecular pathology of the human brain, showing many instructive characteristics. Nevertheless, the developmental profile and distribution of lesions in the rat brain, with neurophysiological and behavioral manifestation, deviate considerably from humans, raising numerous research and translational questions. In this study, we revisit brain TSC in human and Eker rats to relate their histopathological, electrophysiological, and neurobehavioral characteristics. We discuss shared and distinct aspects of the pathology and consider factors contributing to phenotypic discrepancies. Given the shared genetic cause and molecular pathology, phenotypic deviations suggest an incomplete understanding of the disease. Narrowing the knowledge gap in the future should not only improve the characterization of the TSC rat model but also explain considerable variability in the clinical manifestation of the disease in humans.
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- druhová specificita MeSH
- duševní poruchy genetika patologie psychologie MeSH
- fenotyp * MeSH
- hamartin genetika MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- mozek patologie MeSH
- TOR serin-threoninkinasy genetika MeSH
- tuberin genetika MeSH
- tuberózní skleróza genetika patologie psychologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Cíl: Schizofrenie, bipolární afektivní porucha, unipolární deprese a demence u Alzheimerovy choroby mají silný genetický a neurobiologický podklad. Cílem této souhrnné práce je podat stručný přehled současných poznatků o genetice a epigenetice uvedených vážných duševních poruch pro lepší informovanost zájemců o biologickou psychiatrii a další výzkum. Výsledky: Zásadní nové poznatky o genetice vážných duševních poruch přinesly celogenomové asociační studie. U schizofrenie již bylo odhaleno několik desítek bodových polymorfismů DNA, významných pro vznik a rozvoj onemocnění. Ty se podílejí na vývoji mozkových struktur, jejich vzájemném propojení, neuronální komunikaci, imunitní reakci a regulaci exprese DNA. Pokud jde o bipolární afektivní poruchu, významné geny se týkají zejména neuronální konektivity, neuroplasticity a přenosu vzruchu nervovou tkání, zejména kalciové signalizace. V etiologii unipolární deprese jsou významné například geny pro serotoninovou signalizaci a jednotlivé neutropní faktory, dále geny ovlivňující činnost osy hypothalamus-hypofýza-nadledvina a imunitu. Neméně důležité jsou však zevní stresové podněty. U rodinné formy demence u Alzheimerovy choroby mají zásadní význam geny, které se podílejí na tvorbě amyloidu beta. U demence u Alzheimerovy choroby s výskytem sporadickým je jednoznačně významný gen pro apolipoprotein E, rovněž se podílející na tvorbě beta amyloidu. Je však odhalována řada dalších genů ve spojení s imunitou či regulací činnosti DNA. Výsledky doposud publikovaných studií v oblasti epigenetiky vážných duševních poruch akcentují význam methylace DNA, modifikace histonů a tvorby mikroRNA, kde veškeré tyto faktory ovlivňují genovou expresi a následnou tvorbu proteinů. Epigenetické studie však doposud nepřinesly konzistentní poznání v dané oblasti, výzkum je zde spíše na svém počátku. Závěr: Ukazuje se, že genetické a epigenetické příčiny vážných duševních poruch jsou velmi komplexní a zahrnují řadu různých mechanismů. Celogenomové asociační studie byly velkým přínosem v poznání genetické etiologie těchto onemocnění, nicméně neobjasňují následnou patogenezi. Výzkum faktorů epigenetických posunul naše poznání kupředu, avšak jeho výsledky jsou doposud nekonzistentní. Zajímavým je zjištění, že řada epi/genetických nálezů se u jednotlivých duševních poruch překrývá, například mezi schizofrenií a bipolární afektivní poruchou. Lze očekávat, že další rozvoj neurobiologických vyšetřovacích metod a statistických metod problematiku epi/genetiky vážných duševních poruch více ozřejmí.
Objective: Schizophrenia, bipolar affective disorder, major depression and dementia in Alzheimer ́s disease have a strong genetic and neurobiological background. The aim of this review is to briefly sum up recent knowledge on genetics and epigenetics of these serious mental disorders in order to educate professionals in the field of biological psychiatry and stimulate further research. Results: Cardinal new knowledge on the genetics of serious mental disorders was recently brought by whole-genome association studies. Dozens of single nucleotide DNA polymorphisms significantly associated with schizophrenia were detected. These genetic variants are related to the development of brain structures, their interconnection, neural communication, immune reaction and regulation of DNA expression. As of the bipolar affective disorder, significant genes especially apply to neural connectivity, neuroplasticity and neural transmission, in particular calcium signalling. In the etiology of major depression, genes influencing serotonin signalling, neurotrophic substances, the hypothalamus-pituitary-adrenalin axis or immunity are of import. However, external stressful stimuli are also substantial. In the familial form of dementia in Alzheimer ́s disease, the genes participating in the betaamyloid synthesis are of importance. As for the sporadic dementia in Alzheimer's disease, the Apolipoprotein E gene involved in the beta-amyloid formation is definitely relevant. At the same time, several genes linked to immunity or DNA expression regulation are also substantial. The results of the most frequently published epigenetic studies accentuate the significance of DNA methylation, histone modifications and mikroRNAs, when all these factors influence gene expression and subsequently protein synthesis. Unfortunately, epigenetic studies were so far not able to bring consistent results, and epigenetic research of serious mental disorders is more at its beginning than at its end. Conclusion: It becomes apparent that genetic and epigenetic etiology of serious mental disorders is very complex and comprise a whole range of different mechanisms. Whole-genome association studies were a big contribution in our discovery of genetic etiology, but pathogenesis still remains unclear. Epigenetic research partly moved our recognition ahead, but its results are still far from consistency. The interesting fact is that some epi/genetic findings overlap between individual mental disorders, e.g. between schizophrenia and bipolar disorder. It is legitimate to anticipate that new neurobiological examination methods and statistical assessment methods will elucidate the issues of epi/genetics of serious mental disorders in the future.
