NEGR1 and FGFR2 cooperatively regulate cortical development and core behaviours related to autism disorders in mice.
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ABSTRACT:
SUBMITTER: Szczurkowska J
PROVIDER: S-EPMC6113639 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The Negr1 gene has been significantly associated with major depression in genetic studies. Negr1 encodes for a cell adhesion molecule cleaved by the protease Adam10, thus activating Fgfr2 and promoting neuronal spine plasticity. We investigated whether antidepressants modulate the expression of genes belonging to Negr1-Fgfr2 pathway in Flinders sensitive line (FSL) rats, in a corticosterone-treated mouse model of depression, and in mouse primary neurons. Negr1 and Adam10 were the genes mostly affected by antidepressant treatment, and in opposite directions. Negr1 was down-regulated by escitalopram in the hypothalamus of FSL rats, by fluoxetine in the hippocampal dentate gyrus of corticosterone-treated mice, and by nortriptyline in hippocampal primary neurons. Adam10 mRNA was increased by nortriptyline administration in the hypothalamus, by escitalopram in the hippocampus of FSL rats, and by fluoxetine in mouse dorsal dentate gyrus. Similarly, nortriptyline increased Adam10 expression in hippocampal cultures. Fgfr2 expression was increased by nortriptyline in the hypothalamus of FSL rats and in hippocampal neurons. Lsamp, another IgLON family protein, increased in mouse dentate gyrus after fluoxetine treatment. These findings suggest that Negr1-Fgfr2 pathway plays a role in the modulation of synaptic plasticity induced by antidepressant treatment to promote therapeutic efficacy by rearranging connectivity in corticolimbic circuits impaired in depression.
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Project description:BackgroundCopy number variants have emerged as an important genomic cause of common, complex neurodevelopmental disorders. These usually change copy number of multiple genes, but deletions at 2p16.3, which have been associated with autism, schizophrenia and mental retardation, affect only the neurexin 1 gene, usually the alpha isoform. Previous analyses of neurexin 1? (Nrxn1?) knockout (KO) mouse as a model of these disorders have revealed impairments in synaptic transmission but failed to reveal defects in social behaviour, one of the core symptoms of autism.MethodsWe performed a detailed investigation of the behavioural effects of Nrxn1? deletion in mice bred onto a pure genetic background (C57BL/6J) to gain a better understanding of its role in neurodevelopmental disorders. Wildtype, heterozygote and homozygote Nrxn1? KO male and female mice were tested in a battery of behavioural tests (n?=?9-16 per genotype, per sex).ResultsIn homozygous Nrxn1? KO mice, we observed altered social approach, reduced social investigation, and reduced locomotor activity in novel environments. In addition, male Nrxn1? KO mice demonstrated an increase in aggressive behaviours.ConclusionsThese are the first experimental data that associate a deletion of Nrxn1? with alterations of social behaviour in mice. Since this represents one of the core symptom domains affected in autism spectrum disorders and schizophrenia in humans, our findings suggest that deletions within NRXN1 found in patients may be responsible for the impairments seen in social behaviours, and that the Nrxn1? KO mice are a useful model of human neurodevelopmental disorder.
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Project description:IgLON proteins are GPI anchored adhesion molecules that control neurite outgrowth. In particular, Negr1 down-regulation negatively influences neuronal arborization in vitro and in vivo. In the present study, we found that the metalloprotease ADAM10 releases Negr1 from neuronal membrane. Ectodomain shedding influences several neuronal mechanisms, including survival, synaptogenesis, and the formation of neurite trees. By combining morphological analysis and virus-mediated selective protein silencing in primary murine cortical neurons, we found that pharmacologically inhibition of ADAM10 results in an impairment of neurite tree maturation that can be rescued upon treatment with soluble Negr1. Furthermore, we report that released Negr1 influences neurite outgrowth in a P-ERK1/2 and FGFR2 dependent manner. Together our findings suggest a role for Negr1 in regulating neurite outgrowth through the modulation of FGFR2 signaling pathway. Given the physiological and pathological role of ADAM10, Negr1, and FGFR2, the regulation of Negr1 shedding may play a crucial role in sustaining brain function and development.
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Project description:Autism spectrum disorder (ASD) is a heterogeneous disease that is characterized by abnormalities in social communication and interaction as well as repetitive behaviors and restricted interests. Structural brain imaging has identified significant cortical folding alterations in ASD; however, relatively less known is whether the core symptoms are related to neuroanatomical differences. In this study, we aimed to explore core-symptom-anchored gyrification alterations and their developmental trajectories in ASD. We measured the cortical vertex-wise gyrification index (GI) in 321 patients with ASD (aged 7-39 years) and 350 typically developing (TD) subjects (aged 6-33 years) across 8 sites from the Autism Brain Imaging Data Exchange I (ABIDE I) repository and a longitudinal sample (14 ASD and 7 TD, aged 9-14 years in baseline and 12-18 years in follow-up) from ABIDE II. Compared with TD, the general ASD patients exhibited a mixed pattern of both hypo- and hyper- and different developmental trajectories of gyrification. By parsing the ASD patients into three subgroups based on the subscores of the Autism Diagnostic Interview-Revised (ADI-R) scale, we identified core-symptom-specific alterations in the reciprocal social interaction (RSI), communication abnormalities (CA), and restricted, repetitive, and stereotyped patterns of behavior (RRSB) subgroups. We also showed atypical gyrification patterns and developmental trajectories in the subgroups. Furthermore, we conducted a meta-analysis to locate the core-symptom-anchored brain regions (circuits). In summary, the current study shows that ASD is associated with abnormal cortical folding patterns. Core-symptom-based classification can find more subtle changes in gyrification. These results suggest that cortical folding pattern encodes changes in symptom dimensions, which promotes the understanding of neuroanatomical basis, and clinical utility in ASD.
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Project description:In the nervous system, Kirrel3 is involved in neuronal migration, axonal fasciculation, and synapse formation. Recently, genetic links have been reported between mutations in the KIRREL3 gene and increased risk of neurodevelopmental disorders, including autism spectrum disorder (ASD) and intellectual disability. To elucidate the causal relationship between KIRREL3 deficiency and behavioural abnormalities relevant to neurodevelopmental disorders, we generated global Kirrel3-knockout (Kirrel3-/-) mice and investigated the detailed behavioural phenotypes. In the three-chambered social approach test, Kirrel3-/- mice displayed a significant preference for a mouse over a non-social object but no significant preference for a stranger mouse over a familiar mouse. Ultrasonic communications, including pup-to-mother calls, male-female courtship vocalisation and resident responses to intruder, were significantly impaired in Kirrel3-/- mice. Significant increases in locomotor activity and repetitive rearing were also observed in Kirrel3-/- mice. Furthermore, the performance of Kirrel3-/- mice in the rotarod test was significantly better than that of wild-type mice. In the acoustic startle test, Kirrel3-/- mice were significantly hypersensitive to acoustic stimuli. Anxiety-related behaviours and spatial or fear memory acquisition were normal in Kirrel3-/- mice. These findings suggest that Kirrel3-/- mice exhibit autistic-like behaviours, including social and communicative deficits, repetitive behaviours, and sensory abnormalities, as well as hyperactivity.
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Project description:BACKGROUND:Perturbations to the microscopic level balance between synaptic excitation and inhibition and neuron organization in the cerebral cortex are suggested to underlie autism spectrum disorder (ASD) traits. The mechanism linking these perturbations to cognitive behaviors in ASD is unknown. This study strives to bridge this gap by generating clinically testable diagnostic and pharmacological predictions based on the effect of synaptic imbalance and neuron distribution on a computational local circuit model of the cerebral cortex. METHODS:We use a computational microscopic model of the cerebral cortex that incorporates N-methyl-D-aspartate and gamma-aminobutyric acid synaptic kinetics. We employ the model circuit during model tasks similar to visually guided and gap oculomotor saccade tasks and interpret qualitative model predictions of saccade hypometria and dysmetria. We consider the effects of varying the excitatory to inhibitory synaptic balance, neuron density, and neuron clustering in this model. RESULTS:An increase of synaptic excitation over synaptic inhibition results in increased hypometria and dysmetria. Similar effects by either reduced inhibition or increased excitation suggest that a variety of pharmacological compounds can be used for both screening and medical management. On the other hand, any change to the microscopic neuron anatomy that increases the effective maximum distance between excitatory neurons decreases hypometria but has no affect on dysmetria. CONCLUSIONS:Perturbations to a computational model of a local cerebral cortical circuit can account for saccade hypometria and dysmetria reported in ASD studies. This approach may provide a direct link between cerebral cortical function and ASD behaviors.
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Project description:Studies of head size and brain volume in autism spectrum disorders have suggested that early cortical overgrowth may be followed by prematurely arrested growth. However, the few investigations quantifying cortical thickness have yielded inconsistent results, probably due to variable ages and/or small sample sizes. We assessed differences in cortical thickness between high-functioning adolescent and young adult males with autism spectrum disorders (n = 41) and matched typically developing males (n = 40). We hypothesized thinner cortex, particularly in frontal, parietal and temporal regions, for individuals with autism spectrum disorders in comparison with typically developing controls. Furthermore, we expected to find an age × diagnosis interaction: with increasing age, more pronounced cortical thinning would be observed in autism spectrum disorders than typically developing participants. T(1)-weighted magnetization prepared rapid gradient echo 3 T magnetic resonance imaging scans were acquired from high-functioning males with autism spectrum disorders and from typically developing males matched group-wise on age (range 12-24 years), intelligence quotient (≥ 85) and handedness. Both gyral-level and vertex-based analyses revealed significantly thinner cortex in the autism spectrum disorders group that was located predominantly in left temporal and parietal regions (i.e. the superior temporal sulcus, inferior temporal, postcentral/superior parietal and supramarginal gyri). These findings remained largely unchanged after controlling for intelligence quotient and after accounting for psychotropic medication usage and comorbid psychopathology. Furthermore, a significant age × diagnosis interaction was found in the left fusiform/inferior temporal cortex: participants with autism spectrum disorders had thinner cortex in this region with increasing age to a greater degree than did typically developing participants. Follow-up within group comparisons revealed significant age-related thinning in the autism spectrum disorders group but not in the typically developing group. Both thinner temporal and parietal cortices during adolescence and young adulthood and discrepantly accelerated age-related cortical thinning in autism spectrum disorders suggest that a second period of abnormal cortical growth (i.e. greater thinning) may be characteristic of these disorders.
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Project description:BACKGROUND:Challenging behaviours are highly prevalent in children and adolescents with autism spectrum disorders (ASD), but little is known about the prevalence and course of these behaviours during adulthood. The aims of this study were to describe the topography of challenging behaviours in a cohort of 106 young adults with ASD and to identify the risk factors for challenging behaviours. Our secondary objective was to study the changes in challenging behaviours from adolescence to early adult years. METHOD:The present study uses data from the EpiTED prospective follow-up study in France. The presence of challenging behaviours was assessed by the Aberrant Behaviour Checklist (ABC) completed by parent informants. Several dimensions of behaviour were studied: irritability, stereotypy, lethargy, hyperactivity and self-injury. Clinical variables were collected on ASD symptom severity, cognitive and language levels, adaptive behaviours and comorbid medical disorders. RESULTS:The presence of challenging behaviours at early adulthood was related to the young adult's cognitive and language level, ASD symptom severity and comorbid gastrointestinal and sleep disorders. The main risk factor for challenging behaviours was ASD symptom severity. The level of language impairment was a significant predictor of self-injury. Gastrointestinal disorders were a significant predictor of stereotypy. The change in behaviour topography from adolescence to early adult years corresponded with decreased parent report of hyperactivity, but no significant decrease in parent reports of irritability, stereotypy, lethargy and self-injurious behaviours. CONCLUSIONS:The challenging behaviours in individuals with ASD persist in early adulthood and are related to core symptom severity, levels of cognitive and language impairments and medical comorbidity. The results emphasise the importance of early interventions for children with ASD to target cognitive and language abilities and to alleviate the severity of ASD symptoms. They also underscore the need to enhance opportunities for individuals with ASD to better communicate discomforts and pain in the context of medical illness.
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Project description:Analogous to the c-Myc (Myc)/Max family of bHLH-ZIP transcription factors, there exists a parallel regulatory network of structurally and functionally related proteins with Myc-like functions. Two related Myc-like paralogs, termed MondoA and MondoB/carbohydrate response element-binding protein (ChREBP), up-regulate gene expression in heterodimeric association with the bHLH-ZIP Max-like factor Mlx. Myc is necessary to support liver cancer growth, but not for normal hepatocyte proliferation. Here, we investigated ChREBP's role in these processes and its relationship to Myc. Unlike Myc loss, ChREBP loss conferred a proliferative disadvantage to normal murine hepatocytes, as did the combined loss of ChREBP and Myc. Moreover, hepatoblastomas (HBs) originating in myc-/-, chrebp-/-, or myc-/-/chrebp-/- backgrounds grew significantly more slowly. Metabolic studies on livers and HBs in all three genetic backgrounds revealed marked differences in oxidative phosphorylation, fatty acid ?-oxidation (FAO), and pyruvate dehydrogenase activity. RNA-Seq of livers and HBs suggested seven distinct mechanisms of Myc-ChREBP target gene regulation. Gene ontology analysis indicated that many transcripts deregulated in the chrebp-/- background encode enzymes functioning in glycolysis, the TCA cycle, and ?- and ?-FAO, whereas those dysregulated in the myc-/- background encode enzymes functioning in glycolysis, glutaminolysis, and sterol biosynthesis. In the myc-/-/chrebp-/- background, additional deregulated transcripts included those involved in peroxisomal ?- and ?-FAO. Finally, we observed that Myc and ChREBP cooperatively up-regulated virtually all ribosomal protein genes. Our findings define the individual and cooperative proliferative, metabolic, and transcriptional roles for the "Extended Myc Network" under both normal and neoplastic conditions.
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