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.
- Klíčová slova
- Autism spectrum disorders, Cerebellum, Fmr1, Mecp2, Nlgn3/4, Purkinje neurons, Tsc1/2,
- MeSH
- modely genetické MeSH
- modely nemocí na zvířatech * MeSH
- mozeček * patofyziologie patologie MeSH
- poruchy autistického spektra * genetika patologie patofyziologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The heterogeneity of the glioma subtype glioblastoma multiforme (GBM) challenges effective neuropathological treatment. The reliance on in vitro studies and xenografted animal models to simulate human GBM has proven ineffective. Currently, a dearth of knowledge exists regarding the applicability of cell line biomolecules to the realm of GBM pathogenesis. Our study's objectives were to address this preclinical issue and assess prominin-1, ICAM-1, PARTICLE and GAS5 as potential GBM diagnostic targets. The methodologies included haemoxylin and eosin staining, immunofluorescence, in situ hybridization and quantitative PCR. The findings identified that morphology correlates with malignancy in GBM patient pathology. Immunofluorescence confocal microscopy revealed prominin-1 in pseudo-palisades adjacent to necrotic foci in both animal and human GBM. Evidence is presented for an ICAM-1 association with degenerating vasculature. Significantly elevated nuclear PARTICLE expression from in situ hybridization and quantitative PCR reflected its role as a tumor activator. GAS5 identified within necrotic GBM validated this potential prognostic biomolecule with extended survival. Here we present evidence for the stem cell marker prominin-1 and the chemotherapeutic target ICAM-1 in a glioma animal model and GBM pathology sections from patients that elicited alternative responses to adjuvant chemotherapy. This foremost study introduces the long non-coding RNA PARTICLE into the context of human GBM pathogenesis while substantiating the role of GAS5 as a tumor suppressor. The validation of GBM biomarkers from cellular models contributes to the advancement towards superior detection, therapeutic responders and the ultimate attainment of promising prognoses for this currently incurable brain cancer.
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.
- Klíčová slova
- Eker rats, animal models of autism, cingulate gyrus, dendritic spine, enriched environment, open field test, tuberous sclerosis complex,
- MeSH
- hipokampus metabolismus MeSH
- krysa rodu Rattus MeSH
- modely nemocí na zvířatech MeSH
- mTORC1 metabolismus 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
- Názvy látek
- mTORC1 MeSH
The cerebellum hosts more than half of all neurons of the human brain, with their organized activity playing a key role in coordinating motor functions. Cerebellar activity has also been implicated in the control of speech, communication, and social behavior, which are compromised in autism spectrum disorders (ASD). Despite major research advances, there is a shortage of mechanistic data relating cellular and molecular changes in the cerebellum to autistic behavior. We studied the impact of tuberous sclerosis complex 2 haploinsufficiency (Tsc2+/-) with downstream mTORC1 hyperactivity on cerebellar morphology and cellular organization in 1, 9, and 18 m.o. Eker rats, to determine possible structural correlates of an autism-like behavioural phenotype in this model. We report a greater developmental expansion of the cerebellar vermis, owing to enlarged white matter and thickened molecular layer. Histochemical and immunofluorescence data suggest age-related demyelination of central tract of the vermis, as evident from reduced level of myelin-basic protein in the arbora vitae. We also observed a higher number of astrocytes in Tsc2+/- rats of older age while the number of Purkinje cells (PCs) in these animals was lower than in wild-type controls. Unlike astrocytes and PCs, Bergmann glia remained unaltered at all ages in both genotypes, while the number of microglia was higher in Tsc2+/- rats of older age. The convergent evidence for a variety of age-dependent cellular changes in the cerebellum of rats associated with mTORC1 hyperactivity, thus, predicts an array of functional impairments, which may contribute to the developmental onset of an autism-like behavioral phenotype in this model. LAY SUMMARY: This study elucidates the impact of constitutive mTORC1 hyperactivity on cerebellar morphology and cellular organization in a rat model of autism and epilepsy. It describes age-dependent degeneration of Purkinje neurons, with demyelination of central tract as well as activation of microglia, and discusses the implications of these changes for neuro-behavioral phenotypes. The described changes provide new indications for the putative mechanisms underlying cerebellar impairments with their age-related onset, which may contribute to the pathobiology of autism, epilepsy, and related disorders.
- Klíčová slova
- Purkinje neurons, autism spectrum disorder, cerebellum, demyelination, mTORC1 signaling, microglia activation, synaptophysin,
- MeSH
- autistická porucha * MeSH
- demyelinizační nemoci * komplikace metabolismus MeSH
- epilepsie * komplikace MeSH
- fenotyp MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- mozeček metabolismus MeSH
- mTORC1 genetika metabolismus MeSH
- poruchy autistického spektra * MeSH
- tuberózní skleróza MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- mTORC1 MeSH
Notwithstanding major advances in psychotherapeutics, their efficacy and specificity remain limited. The slow onset of beneficial outcomes and numerous adverse effects of widely used medications remain of chief concern, warranting in-depth studies. The majority of frontline therapies are thought to enhance the endogenous monoaminergic drive, to initiate a cascade of molecular events leading to lasting functional and structural plasticity. They also involve alterations in trophic factor signalling, including brain-derived neurotrophic factor (BDNF), VGF (non-acronymic), vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), glial cell-derived neurotrophic factor (GDNF), and others. In several major mental disorders, emerging data suggest protective and restorative effects of trophic factors in preclinical models, when applied on their own. Antidepressant outcomes of VGF and FGF2, for instance, were shown in experimental animals, while BDNF and GDNF prove useful in the treatment of addiction, schizophrenia, and autism spectrum disorders. The main challenge with the effective translation of these and other findings in the clinic is the knowledge gap in action mechanisms with potential risks, as well as the lack of effective platforms for validation under clinical settings. Herein, we review the state-of-the-art and advances in the therapeutic use of trophic factors in several major neuropsychiatric disorders.
- Klíčová slova
- Antidepressants, Antipsychotics, Growth factor, Neuropsychiatry, Polyplex nanoparticles, Targeted delivery,
- MeSH
- duševní poruchy farmakoterapie MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- nanočásticový lékový transportní systém * MeSH
- neuroplasticita účinky léků MeSH
- neurotrofní faktory aplikace a dávkování MeSH
- přehledová literatura jako téma MeSH
- preklinické hodnocení léčiv MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- nanočásticový lékový transportní systém * MeSH
- neurotrofní faktory MeSH
The autoimmune condition, Celiac Disease (CeD), displays broad clinical symptoms due to gluten exposure. Its genetic association with DQ variants in the human leukocyte antigen (HLA) system has been recognised. Monocyte-derived mature dendritic cells (MoDCs) present gluten peptides through HLA-DQ and co-stimulatory molecules to T lymphocytes, eliciting a cytokine-rich microenvironment. Having access to CeD associated families prevalent in the Czech Republic, this study utilised an in vitro model to investigate their differential monocyte profile. The higher monocyte yields isolated from PBMCs of CeD patients versus control individuals also reflected the greater proportion of dendritic cells derived from these sources following lipopolysaccharide (LPS)/ peptic-tryptic-gliadin (PTG) fragment stimulation. Cell surface markers of CeD monocytes and MoDCs were subsequently profiled. This foremost study identified a novel bio-profile characterised by elevated CD64 and reduced CD33 levels, unique to CD14++ monocytes of CeD patients. Normalisation to LPS stimulation revealed the increased sensitivity of CeD-MoDCs to PTG, as shown by CD86 and HLA-DQ flow cytometric readouts. Enhanced CD86 and HLA-DQ expression in CeD-MoDCs were revealed by confocal microscopy. Analysis highlighted their dominance at the CeD-MoDC membrane in comparison to controls, reflective of superior antigen presentation ability. In conclusion, this investigative study deciphered the monocytes and MoDCs of CeD patients with the identification of a novel bio-profile marker of potential diagnostic value for clinical interpretation. Herein, the characterisation of CD86 and HLA-DQ as activators to stimulants, along with robust membrane assembly reflective of efficient antigen presentation, offers CeD targeted therapeutic avenues worth further exploration.
- Klíčová slova
- CD33, CD64, CD86, MHCDQ, autoimmunity, major histocompatibility complex II, monocyte, monocyte-derived dendritic cells,
- MeSH
- autoimunitní nemoci imunologie MeSH
- biologické markery metabolismus MeSH
- buněčná membrána metabolismus MeSH
- CD antigeny metabolismus MeSH
- celiakie epidemiologie imunologie MeSH
- cytotoxické T-lymfocyty imunologie MeSH
- dendritické buňky imunologie MeSH
- dospělí MeSH
- gliadin škodlivé účinky MeSH
- HLA-DQ antigeny metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- lipopolysacharidy MeSH
- mladiství MeSH
- mladý dospělý MeSH
- monocyty metabolismus MeSH
- náchylnost k nemoci MeSH
- prezentace antigenu imunologie MeSH
- rodina MeSH
- rodokmen MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika epidemiologie MeSH
- Názvy látek
- biologické markery MeSH
- CD antigeny MeSH
- gliadin MeSH
- HLA-DQ antigeny MeSH
- lipopolysacharidy MeSH
Glioblastoma multiforme (GBM) is a primary brain cancer of poor prognosis, with existing treatments remaining essentially palliative. Current GBM therapy fails due to rapid reappearance of the heterogeneous neoplasm, with models suggesting that the recurrent growth is from treatment-resistant glioblastoma stem-like cells (GSCs). Whether GSCs depend on survival/proliferative cues from their surrounding microenvironmental niche, particularly surrounding the leading edge after treatment remains unknown. Simulating human GBM in the laboratory relies on representative cell lines and xenograft models for translational medicine. Due to U87MG source discrepancy and differential proliferation responses to retinoic acid treatment, this study highlights the challenges faced by laboratory scientists working with this representative GBM cell line. Investigating the response to all trans-retinoic acid (ATRA) revealed its sequestering of the prominin-1 stem cell marker. ICAM-1 universally present throughout U87MG was enhanced by ATRA, of interest for chemotherapy targeting studies. ATRA triggered diverse expression patterns of long non-coding RNAs PARTICLE and GAS5 in the leading edge and established monolayer growth zone microenvironment. Karyotyping confirmed the female origin of U87MG sourced from Europe. Passaging U87MG revealed the presence of chromosomal anomalies reflective of structural genomic alterations in this glioblastoma cell line. All evidence considered, this study exposes further phenotypic nuances of U87MG which may belie researchers seeking data contributing towards the elusive cure for GBM.
- Klíčová slova
- ATRA, CD54, brain cancer, chromosome, lncRNA, prominin-1,
- Publikační typ
- časopisecké články MeSH
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.
- Klíčová slova
- TSC1, TSC2, autism spectrum disorders, hamartoma, mTOR signaling, neoplasia, refractory epilepsy,
- MeSH
- 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
- Názvy látek
- hamartin MeSH
- MTOR protein, human MeSH Prohlížeč
- TOR serin-threoninkinasy MeSH
- tuberin MeSH
Maternal immune activation (MIA) during pregnancy represents an important environmental factor in the etiology of schizophrenia and autism spectrum disorders (ASD). Our goal was to investigate the impacts of MIA on the brain and behavior of adolescent and adult offspring, as a rat model of these neurodevelopmental disorders. We injected bacterial lipopolysaccharide (LPS, 1 mg/kg) to pregnant Wistar dams from gestational day 7, every other day, up to delivery. Behavior of the offspring was examined in a comprehensive battery of tasks at postnatal days P45 and P90. Several brain parameters were analyzed at P28. The results showed that prenatal immune activation caused social and communication impairments in the adult offspring of both sexes; males were affected already in adolescence. MIA also caused prepulse inhibition deficit in females and increased the startle reaction in males. Anxiety and hypolocomotion were apparent in LPS-affected males and females. In the 28-day-old LPS offspring, we found enlargement of the brain and decreased numbers of parvalbumin-positive interneurons in the frontal cortex in both sexes. To conclude, our data indicate that sex of the offspring plays a crucial role in the development of the MIA-induced behavioral alterations, whereas changes in the brain apparent in young animals are sex-independent.
- Klíčová slova
- autism, chronic bacterial infection, development, lipopolysaccharide, macrocephaly, maternal immune activation, parvalbumin-positive interneurons, prenatal infection, schizophrenia, sex differences,
- MeSH
- chování zvířat * MeSH
- imunohistochemie MeSH
- imunomodulace * MeSH
- interneurony metabolismus MeSH
- krysa rodu Rattus MeSH
- lipopolysacharidy imunologie MeSH
- matka - expozice noxám MeSH
- mikroglie imunologie metabolismus MeSH
- mozek imunologie metabolismus MeSH
- parvalbuminy metabolismus MeSH
- sexuální faktory MeSH
- sociální chování MeSH
- těhotenství MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- lipopolysacharidy MeSH
- parvalbuminy MeSH
Tuberous sclerosis complex (TSC) is a genetic disorder characterized by frequent noncancerous neoplasia in the brain, which can induce a range of severe neuropsychiatric symptoms in humans, resulting from out of control tissue growth. The causative spontaneous loss-of-function mutations have been also identified in rats. Herein, we studied histopathological and molecular changes in brain lesions of the Eker rat model carrying germline mutation of the tsc2 gene, predisposed to multiple neoplasias. Predominant subcortical tumors were analyzed, along with a rare form occurring within the pyriform lobe. The uniform composition of lesions supports the histochemical parity of malformations, with immunofluorescence data supporting their neuro-glial origin. Massive depletion of mature neurons and axonal loss were evident within lesions, with occasional necrotic foci implying advanced stage of pathology. Enrichment of mesenchymal-derived cell markers with hallmarks of neurogenesis and active microglia imply enhanced cell proliferation, with local immune response. The depletion of capillaries within the core was complemented by the formation of dense mesh of nascent vessels at the interface of neoplasia with healthy tissue, implying large-scale vascular remodeling. Taken as a whole, these findings present several novel features of brain tumors in Eker rat model, rendering it suitable for studies of the pathobiology and progression of primary brain tumors, with therapeutic interventions.
- Klíčová slova
- Eker rat, Glioma, Hamartomas, Microglial activation, Nascent capillaries, Neuro-oncology, Tuberous sclerosis complex,
- MeSH
- astrocyty patologie MeSH
- axony patologie MeSH
- mikroglie patologie MeSH
- mozek krevní zásobení patologie MeSH
- nádory mozku krevní zásobení etiologie patologie MeSH
- neurony patologie MeSH
- potkani Long-Evans MeSH
- remodelace cév * MeSH
- tuberin genetika MeSH
- tuberózní skleróza komplikace patologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- Tsc2 protein, rat MeSH Prohlížeč
- tuberin MeSH
