Functional and molecular alterations in the cerebellum are among the most widely recognised associates of autism spectrum disorders (ASD). As a critical computational hub of the brain, the cerebellum controls and coordinates a range of motor, affective and cognitive processes. Despite well-described circuits and integrative mechanisms, specific changes that underlie cerebellar impairments in ASD remain elusive. Studies in experimental animals have been critical in uncovering molecular pathology and neuro-behavioural correlates, providing a model for investigating complex disease conditions. Herein, we review commonalities and differences of the most extensively characterised genetic lines of ASD with reference to the cerebellum. We revisit structural, functional, and molecular alterations which may contribute to neurobehavioral phenotypes. The cross-model analysis of this study provides an integrated outlook on the role of cerebellar alterations in pathobiology of ASD that may benefit future translational research and development of therapies.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder accompanied by narrow interests, difficulties in communication and social interaction, and repetitive behavior. In addition, ASD is frequently associated with eating and feeding problems. Although the symptoms of ASD are more likely to be observed in boys, the prevalence of eating disorders is more common in females. The ingestive behavior is regulated by the integrative system of the brain, which involves both homeostatic and hedonic neural circuits. Sex differences in the physiology of food intake depend on sex hormones regulating the expression of the ASD-associated Shank genes. Shank3 mutation leads to ASD-like traits and Shank3B -/- mice have been established as an animal model to study the neurobiology of ASD. Therefore, the long-lasting neuronal activity in the central neural circuit related to the homeostatic and hedonic regulation of food intake was evaluated in both sexes of Shank3B mice, followed by the evaluation of the food intake and preference. In the Shank3B +/+ genotype, well-preserved relationships in the tonic activity within the homeostatic neural network together with the relationships between ingestion and hedonic preference were observed in males but were reduced in females. These interrelations were partially or completely lost in the mice with the Shank3B -/- genotype. A decreased hedonic preference for the sweet taste but increased total food intake was found in the Shank3B -/- mice. In the Shank3B -/- group, there were altered sex differences related to the amount of tonic cell activity in the hedonic and homeostatic neural networks, together with altered sex differences in sweet and sweet-fat solution intake. Furthermore, the Shank3B -/- females exhibited an increased intake and preference for cheese compared to the Shank3B +/+ ones. The obtained data indicate altered functional crosstalk between the central homeostatic and hedonic neural circuits involved in the regulation of food intake in ASD.
- MeSH
- homeostáza * fyziologie MeSH
- mikrofilamentové proteiny * genetika metabolismus MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- pohlavní dimorfismus * MeSH
- poruchy autistického spektra * genetika metabolismus MeSH
- preference v jídle fyziologie MeSH
- přijímání potravy * fyziologie genetika MeSH
- proteiny nervové tkáně * genetika MeSH
- protoonkogenní proteiny c-fos metabolismus biosyntéza MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Autism spectrum disorder (ASD) is a neurodevelopmental condition causing a range of social and communication impairments. Although the role of multiple genes and environmental factors has been reported, the effects of the interplay between genes and environment on the onset and progression of the disease remains elusive. We housed wild-type (Tsc2+/+) and tuberous sclerosis 2 deficient (Tsc2+/-) Eker rats (ASD model) in individually ventilated cages or enriched conditions and conducted a series of behavioural tests followed by the histochemical analysis of dendritic spines and plasticity in three age groups (days 45, 90 and 365). The elevated plus-maze test revealed a reduction of anxiety by enrichment, whereas the mobility of young and adult Eker rats in the open field was lower compared to the wild type. In the social interaction test, an enriched environment reduced social contact in the youngest group and increased anogenital exploration in 90- and 365-day-old rats. Self-grooming was increased by environmental enrichment in young and adult rats and decreased in aged Eker rats. Dendritic spine counts revealed an increased spine density in the cingulate gyrus in adult Ekers irrespective of housing conditions, whereas spine density in hippocampal pyramidal neurons was comparable across all genotypes and groups. Morphometric analysis of dendritic spines revealed age-related changes in spine morphology and density, which were responsive to animal genotype and environment. Taken together, our findings suggest that under TSC2 haploinsufficiency and mTORC1 hyperactivity, the expression of behavioural signs and neuroplasticity in Eker rats can be differentially influenced by the developmental stage and environment.
- MeSH
- hipokampus metabolismus MeSH
- krysa rodu rattus MeSH
- mechanistické cílové místo rapamycinového komplexu 1 metabolismus MeSH
- modely nemocí na zvířatech MeSH
- neuroplasticita MeSH
- poruchy autistického spektra * genetika metabolismus MeSH
- pyramidové buňky metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Angelman syndrome (AS) is a neurodevelopmental disorder caused by deficits in maternally inherited UBE3A. The disease is characterized by intellectual disability, impaired motor skills, and behavioral deficits, including increased anxiety and autism spectrum disorder features. The mouse models used so far in AS research recapitulate most of the cardinal AS characteristics. However, they do not mimic the situation found in the majority of AS patients who have a large deletion spanning 4-6 Mb. There is also a large variability in phenotypes reported in the available models, which altogether limits development of therapeutics. Therefore, we have generated a mouse model in which the Ube3a gene is deleted entirely from the 5' UTR to the 3' UTR of mouse Ube3a isoform 2, resulting in a deletion of 76 kb. To investigate its phenotypic suitability as a model for AS, we employed a battery of behavioral tests directed to reveal AS pathology and to find out whether this model better mirrors AS development compared to other available models. We found that the maternally inherited Ube3a-deficient line exhibits robust motor dysfunction, as seen in the rotarod and DigiGait tests, and displays abnormalities in additional behavioral paradigms, including reduced nest building and hypoactivity, although no apparent cognitive phenotype was observed in the Barnes maze and novel object recognition tests. The AS mice did, however, underperform in more complex cognition tasks, such as place reversal in the IntelliCage system, and exhibited a different circadian rhythm activity pattern. We show that the novel UBE3A-deficient model, based on a whole-gene deletion, is suitable for AS research, as it recapitulates important phenotypes characteristic of AS. This new mouse model provides complementary possibilities to study the Ube3a gene and its function in health and disease as well as possible therapeutic interventions to restore function.
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.
- MeSH
- 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
BACKGROUND: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life. METHODS: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed. RESULTS: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth. CONCLUSIONS: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy.
- MeSH
- bipolární porucha * MeSH
- depresivní porucha unipolární * patologie MeSH
- dítě MeSH
- hyperkinetická porucha * MeSH
- lidé MeSH
- magnetická rezonanční tomografie metody MeSH
- mozková kůra MeSH
- novorozenec MeSH
- poruchy autistického spektra * genetika patologie MeSH
- předčasný porod * patologie MeSH
- těhotenství MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- novorozenec MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Research Support, N.I.H., Extramural MeSH
Závěrečná zpráva o řešení grantu Agentury pro zdravotnický výzkum MZ ČR
Nestr.
From the genetics perspective intellectual disability and autism spectrum disorders are a large heterogeneous group of rare diseases. Exomes will be sequenced in about 100 families with sporadic or familial occurrence of affected children. Variants will be evaluated using all inheritance models and criteria for pathogenicity. Variants in validated causal genes will be found and used clinically in the families. For variants in candidate genes, other patients with variants in the genes will be searched in other cohorts worldwide. Their existence, phenotypic similarity and functional studies can lead to validation of new causal genes. New patients with variants in rarely mutated genes contribute to the genotype-phenotype correlation. A database of common Czech benign population variants will be assembled. Analyses of gene panels, exomes and genomes will be compared. Optimisation of extant pipelines and other experience gained in the research setting (informed consent, attitudes towards uncertainty, incidentalome etc.) will help in the implementation of these methods in routine practi...
Mentální retardace a poruchy autistického spektra jsou z hlediska genetiky velkou heterogenní skupinou mnoha vzácných onemocnění. Budou sekvenovány exomy u asi 100 rodin s postiženými dětmi se sporadickým i familiálním výskytem. Varianty budou hodnoceny podle různých modelů dědičnosti a kritérií pro posouzení patogenity. Budou odhaleny varianty v již validovaných kauzálních genech, které budou v rodinách klinicky využity, a varianty v kandidátních genech, u kterých budou hledáni v jiných kohortách ve světě pacienti s variantami v týchž genech. Jejich existence, podobnost fenotypů a funkční studie mohou vést k validaci nových kauzálních genů. Popis nových pacientů s variantami ve vzácně mutovaných genech upřesní korelaci genotyp-fenotyp. Bude sestavena databáze častých českých benigních populačních variant. Bude porovnána analýza panelů genů, exomů a genomů. Optimalizace stávajících laboratorních a bioinformatických postupů a další zkušenosti získané ve výzkumném uspořádání (informovaný souhlas, postoje k nejistotě, incidentalomu atd.) pomohou v zavádění těchto metod do rutinní pra...
- MeSH
- exom genetika MeSH
- fenotyp MeSH
- genetická variace genetika MeSH
- genetické testování metody MeSH
- genotyp MeSH
- lidé MeSH
- mentální retardace genetika MeSH
- poruchy autistického spektra genetika MeSH
- výpočetní biologie metody MeSH
- vysoce účinné nukleotidové sekvenování metody MeSH
- Check Tag
- lidé MeSH
- Konspekt
- Patologie. Klinická medicína
- NLK Obory
- genetika, lékařská genetika
- psychiatrie
- NLK Publikační typ
- závěrečné zprávy o řešení grantu AZV MZ ČR
BACKGROUND: One of the most unusual sources of phylogenetically restricted genes is the molecular domestication of transposable elements into a host genome as functional genes. Although these kinds of events are sometimes at the core of key macroevolutionary changes, their origin and organismal function are generally poorly understood. RESULTS: Here, we identify several previously unreported transposable element domestication events in the human and mouse genomes. Among them, we find a remarkable molecular domestication that gave rise to a multigenic family in placental mammals, the Bex/Tceal gene cluster. These genes, which act as hub proteins within diverse signaling pathways, have been associated with neurological features of human patients carrying genomic microdeletions in chromosome X. The Bex/Tceal genes display neural-enriched patterns and are differentially expressed in human neurological disorders, such as autism and schizophrenia. Two different murine alleles of the cluster member Bex3 display morphological and physiopathological brain modifications, such as reduced interneuron number and hippocampal electrophysiological imbalance, alterations that translate into distinct behavioral phenotypes. CONCLUSIONS: We provide an in-depth understanding of the emergence of a gene cluster that originated by transposon domestication and gene duplication at the origin of placental mammals, an evolutionary process that transformed a non-functional transposon sequence into novel components of the eutherian genome. These genes were integrated into existing signaling pathways involved in the development, maintenance, and function of the CNS in eutherians. At least one of its members, Bex3, is relevant for higher brain functions in placental mammals and may be involved in human neurological disorders.
- MeSH
- CRISPR-Cas systémy MeSH
- DNA vazebné proteiny genetika MeSH
- domestikace * MeSH
- fylogeneze MeSH
- jaderné proteiny genetika MeSH
- lidé MeSH
- molekulární evoluce MeSH
- mozek MeSH
- multigenová rodina * MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- neurovývojové poruchy genetika MeSH
- placenta MeSH
- placentálové genetika MeSH
- poruchy autistického spektra genetika MeSH
- proteiny nervové tkáně genetika MeSH
- proteiny regulující apoptózu genetika MeSH
- těhotenství MeSH
- TOR serin-threoninkinasy genetika MeSH
- transkripční faktory genetika MeSH
- transpozibilní elementy DNA * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The role of glutathione in autism spectrum disorder (ASD) is emerging as a major topic, due to its role in the maintenance of the intracellular redox balance. Several studies have implicated glutathione redox imbalance as a leading factor in ASD, and both ASD and many other neurodevelopmental disorders involve low levels of reduced glutathione (GSH), high levels of oxidized glutathione (GSSG), and abnormalities in the expressions of glutathione-related enzymes in the blood or brain. Glutathione metabolism, through its impact on redox environment or redox-independent mechanisms, interferes with multiple mechanisms involved in ASD pathogenesis. Glutathione-mediated regulation of glutamate receptors [e.g., N-methyl-d-aspartate (NMDA) receptor], as well as the role of glutamate as a substrate for glutathione synthesis, may be involved in the regulation of glutamate excitotoxicity. However, the interaction between glutathione and glutamate in the pathogenesis of brain diseases may vary from synergism to antagonism. Modulation of glutathione is also associated with regulation of redox-sensitive transcription factors nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1) and downstream signaling (proinflammatory cytokines and inducible enzymes), thus providing a significant impact on neuroinflammation. Mitochondrial dysfunction, as well as neuronal apoptosis, may also provide a significant link between glutathione metabolism and ASD. Furthermore, it has been recently highlighted that glutathione can affect and modulate DNA methylation and epigenetics. Review analysis including research studies meeting the required criteria for analysis showed statistically significant differences between the plasma GSH and GSSG levels as well as GSH:GSSG ratio in autistic patients compared with healthy individuals (P = 0.0145, P = 0.0150 and P = 0.0202, respectively). Therefore, the existing data provide a strong background on the role of the glutathione system in ASD pathogenesis. Future research is necessary to investigate the role of glutathione redox signaling in ASD, which could potentially also lead to promising therapeutics.
Given our recent discovery of somatic mutations in autism spectrum disorder (ASD)/intellectual disability (ID) genes in postmortem aged Alzheimer's disease brains correlating with increasing tauopathy, it is important to decipher if tauopathy is underlying brain imaging results of atrophy in ASD/ID children. We concentrated on activity-dependent neuroprotective protein (ADNP), a prevalent autism gene. The unique availability of multiple postmortem brain sections of a 7-year-old male, heterozygous for ADNP de novo mutation c.2244Adup/p.His559Glnfs*3 allowed exploration of tauopathy, reflecting on a general unexplored mechanism. The tested subject exhibited autism, fine motor delays, severe intellectual disability and seizures. The patient died after multiple organ failure following liver transplantation. To compare to other ADNP syndrome mutations, immortalized lymphoblastoid cell lines from three different patients (including ADNP p.Arg216*, p.Lys408Valfs*31, and p.Tyr719* heterozygous dominant mutations) and a control were subjected to RNA-seq. Immunohistochemistry, high-throughput gene expression profiles in numerous postmortem tissues followed. Comparisons to a control brain and to extensive datasets were used. Live cell imaging investigated Tau-microtubule interaction, protecting against tauopathy. Extensive child brain tauopathy paralleled by multiple gene expression changes was discovered. Tauopathy was explained by direct mutation effects on Tau-microtubule interaction and correction by the ADNP active snippet NAP. Significant pathway changes (empirical P value < 0.05) included over 100 genes encompassing neuroactive ligand-receptor and cytokine-cytokine receptor interaction, MAPK and calcium signaling, axon guidance and Wnt signaling pathways. Changes were also seen in steroid biosynthesis genes, suggesting sex differences. Selecting the most affected genes by the ADNP mutations for gene expression analysis, in multiple postmortem tissues, identified Tau (MAPT)-gene-related expression changes compared with extensive normal gene expression (RNA-seq) databases. ADNP showed relatively reduced expression in the ADNP syndrome cerebellum, which was also observed for 25 additional genes (representing >50% of the tested genes), including NLGN1, NLGN2, PAX6, SMARCA4, and SNAP25, converging on nervous system development and tauopathy. NAP provided protection against mutated ADNP disrupted Tau-microtubule association. In conclusion, tauopathy may explain brain-imaging findings in ADNP syndrome children and may provide a new direction for the development of tauopathy protecting drug candidates like NAP in ASD/ID.
- MeSH
- autistická porucha * MeSH
- biologické markery MeSH
- dítě MeSH
- DNA-helikasy MeSH
- homeodoménové proteiny metabolismus MeSH
- jaderné proteiny MeSH
- lidé MeSH
- mozek diagnostické zobrazování metabolismus MeSH
- poruchy autistického spektra * genetika MeSH
- proteiny nervové tkáně MeSH
- senioři MeSH
- tauopatie * genetika MeSH
- transkripční faktory MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
