Construct Validity and Cross Validity of a Test Battery Modeling Autism Spectrum Disorder (ASD) in Mice

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Biogenic amines and their metabolites are differentially affected in the Mecp2-deficient mouse brain

International audienceBACKGROUND: Rett syndrome (RTT, MIM #312750) is a severe neurological disorder caused by mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene. Female patients are affected with an incidence of 1/15000 live births and develop normally from birth to 6-18 months of age before the onset of deficits in autonomic, cognitive, motor functions (stereotypic hand movements, impaired locomotion) and autistic features. Studies on Mecp2 mouse models, and specifically null mice, revealed morphological and functional alterations of neurons. Several functions that are regulated by bioaminergic nuclei or peripheral ganglia are impaired in the absence of Mecp2. RESULTS: Using high performance liquid chromatography, combined with electrochemical detection (HPLC/EC) we found that Mecp2(-/y) mice exhibit an alteration of DA metabolism in the ponto-bulbar region at 5 weeks followed by a more global alteration of monoamines when the disease progresses (8 weeks). Hypothalamic measurements suggest biphasic disturbances of norepinephrine and serotonin at pathology onset (5 weeks) that were found stabilized later on (8 weeks). Interestingly, the postnatal nigrostriatal dopaminergic deficit identified previously does not parallel the reduction of the other neurotransmitters investigated. Finally, dosage in cortical samples do not suggest modification in the monoaminergic content respectively at 5 and 8 weeks of age. CONCLUSIONS: We have identified that the level of catecholamines and serotonin is differentially affected in Mecp2(-/y) brain areas in a time-dependent fashion

Biogenic amines and their metabolites are differentially affected in the <it>Mecp2</it>-deficient mouse brain

Abstract Background Rett syndrome (RTT, MIM #312750) is a severe neurological disorder caused by mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene. Female patients are affected with an incidence of 1/15000 live births and develop normally from birth to 6-18 months of age before the onset of deficits in autonomic, cognitive, motor functions (stereotypic hand movements, impaired locomotion) and autistic features. Studies on Mecp2 mouse models, and specifically null mice, revealed morphological and functional alterations of neurons. Several functions that are regulated by bioaminergic nuclei or peripheral ganglia are impaired in the absence of Mecp2. Results Using high performance liquid chromatography, combined with electrochemical detection (HPLC/EC) we found that Mecp2-/y mice exhibit an alteration of DA metabolism in the ponto-bulbar region at 5 weeks followed by a more global alteration of monoamines when the disease progresses (8 weeks). Hypothalamic measurements suggest biphasic disturbances of norepinephrine and serotonin at pathology onset (5 weeks) that were found stabilized later on (8 weeks). Interestingly, the postnatal nigrostriatal dopaminergic deficit identified previously does not parallel the reduction of the other neurotransmitters investigated. Finally, dosage in cortical samples do not suggest modification in the monoaminergic content respectively at 5 and 8 weeks of age. Conclusions We have identified that the level of catecholamines and serotonin is differentially affected in Mecp2-/y brain areas in a time-dependent fashion.</p

Progressive motor and respiratory metabolism deficits in post-weaning Mecp2-null male mice

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Morphological and functional alterations in the substantia nigra pars compacta of the Mecp2-null mouse

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GABA and Glutamate Pathways Are Spatially and Developmentally Affected in the Brain of Mecp2-Deficient Mice

International audienceProper brain functioning requires a fine-tuning between excitatory and inhibitory neurotransmission, a balance maintained through the regulation and release of glutamate and GABA. Rett syndrome (RTT) is a rare genetic disorder caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene affecting the postnatal brain development. Dysfunctions in the GABAergic and glutamatergic systems have been implicated in the neuropathology of RTT and a disruption of the balance between excitation and inhibition, together with a perturbation of the electrophysiological properties of GABA and glutamate neurons, were reported in the brain of the Mecp2-deficient mouse. However, to date, the extent and the nature of the GABA/glutamate deficit affecting the Mecp2-deficient mouse brain are unclear. In order to better characterize these deficits, we simultaneously analyzed the GABA and glutamate levels in Mecp2-deficient mice at 2 different ages (P35 and P55) and in several brain areas. We used a multilevel approach including the quantification of GABA and glutamate levels, as well as the quantification of the mRNA and protein expression levels of key genes involved in the GABAergic and glutamatergic pathways. Our results show that Mecp2-deficient mice displayed regional-and age-dependent variations in the GABA pathway and, to a lesser extent, in the glutamate pathway. The implication of the GABA pathway in the RTT neuropathology was further confirmed using an in vivo treatment with a GABA reuptake inhibitor that significantly improved the lifespan of Mecp2-deficient mice. Our results confirm that RTT mouse present a deficit in the GABAergic pathway and suggest that GABAergic modulators could be interesting therapeutic agents for this severe neurological disorder

Cardiopharyngeal Mesoderm specification into cardiac and skeletal muscle lineages in gastruloids

Abstract Cardiopharyngeal mesoderm contributes to the formation of the heart and head muscles. However, the mechanisms governing cardiopharyngeal mesoderm specification remain unclear. Indeed, there is a lack of an in vitro model replicating the differentiation of both heart and head muscles to study these mechanisms. Such models are required to allow live-imaging and high throughput genetic and drug screening. Here, we show that the formation of self-organizing or pseudo-embryos from mouse embryonic stem cells (mESCs), also called gastruloids, reproduces cardiopharyngeal mesoderm specification towards cardiac and skeletal muscle lineages. By conducting a comprehensive temporal analysis of cardiopharyngeal mesoderm establishment and differentiation in gastruloids and comparing it to mouse embryos, we present the first evidence for skeletal myogenesis in gastruloids. By inferring lineage trajectories from the gastruloids single-cell transcriptomic data, we further suggest that heart and head muscles formed in gastruloids derive from cardiopharyngeal mesoderm progenitors. We identify different subpopulations of cardiomyocytes and skeletal muscles, which most likely correspond to different states of myogenesis with “head-like” and “trunk-like” skeletal myoblasts. These findings unveil the potential of mESC-derived gastruloids to undergo specification into both cardiac and skeletal muscle lineages, allowing the investigation of the mechanisms of cardiopharyngeal mesoderm differentiation in development and how this could be affected in congenital diseases

Neurochemical analysis of the GABA levels in A, the motor cortex; B, caudate-putamen; C, hippocampus; D, hypothalamus; E, substantia nigra pars reticulata; F, brainstem; G, cerebellum; H, spinal cord in P35 <i>Mecp2-</i>deficient (dashed/white bars) and WT (dashed/grey bars) (n = 6 <i>Mecp2^-/y</i>, n = 9 WT for caudate-putamen, motor cortex, hypothalamus and brainstem/n = 6 <i>Mecp2^-/y</i>, n = 6 WT for hippocampus, substantia nigra pars reticulata, cerebelum and spinal cord) and P55 <i>Mecp2^-/y</i> (white bars) and WT (grey bars) mice dosage (n = 9 <i>Mecp2^-/y</i>, n = 8 WT for motor cortex, hypothalamus and brainstem/n = 9 <i>Mecp2^-/y</i>, n = 7 WT for caudate-putamen/n = 5 <i>Mecp2^-/y</i>, n = 6 WT for hippocampus, substantia nigra pars reticulata, cerebellum, spinal cord).

<p>Results are expressed as mean ± S.E.M., (*<i>P</i><0.05, **<i>P</i><0.01, ***<i>P</i><0.001).</p

Developmental changes (P55 vs P35) in GABA concentrations in <i>Mecp2</i>-deficient or wild type mice.

<p><i>Data for each group (WT or Mecp2^-/y) was statistically analyzed by a one-way</i> ANOVA (P55 vs P35) and <i>P</i>-values are shown is parenthesis.</p><p>n.s, non-significant.</p

Differential Brain, Cognitive and Motor Profiles Associated with Partial Trisomy. Modeling Down Syndrome in Mice

International audienceWe hypothesize that the trisomy 21 (Down syndrome) is the additive and interactive outcome of the triple copy of different regions of HSA21. Because of the small number of patients with partial trisomy 21, we addressed the question in the Mouse in which three chromosomal regions located on MMU10, MMU17 and MMU16 carries almost all the HSA21 homologs. Male mice from four segmental trisomic strains covering the D21S17-ETS2 (syntenic to MMU16) were examined with an exhaustive battery of cognitive tests, motor tasks and MRI and compared with TS65Dn that encompasses D21S17-ETS2. None of the four strains gather all the impairments (measured by the effect size) of TS65Dn strain. The 152F7 strain was close to TS65Dn for motor behavior and reference memory and the three other strains 230E8, 141G6 and 285E6 for working memory. Episodic memory was impaired only in strain 285E6. The hippocampus and cerebellum reduced sizes that were seen in all the strains indicate that trisomy 21 is not only a hippocampus syndrome but that it results from abnormal interactions between the two structures