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Detection of neurophysiological features in female R255X MeCP2 mutation mice.

ABSTRACT: Rett syndrome (RTT) is a severe neurodevelopmental disorder (NDD) that is nearly always caused by loss of function mutations in Methyl-CpG-binding Protein 2 (MECP2) and shares many clinical features with other NDD. Genetic restoration of Mecp2 in symptomatic mice lacking MeCP2 expression can reverse symptoms, providing hope that disease modifying therapies can be identified for RTT. Effective and rapid clinical trial completion relies on well-defined clinical outcome measures and robust biomarkers of treatment responses. Studies on other NDD have found evidence of differences in neurophysiological measures that correlate with disease severity. However, currently there are no well-validated biomarkers in RTT to predict disease prognosis or treatment responses. To address this, we characterized neurophysiological features in a mouse model of RTT containing a knock-in nonsense mutation (p.R255X) in the Mecp2 locus. We found a variety of changes in heterozygous female Mecp2^R255X/X mice including age-related changes in sleep/wake architecture, alterations in baseline EEG power, increased incidence of spontaneous epileptiform discharges, and changes in auditory evoked potentials. Furthermore, we identified association of some neurophysiological features with disease severity. These findings provide a set of potential non-invasive and translatable biomarkers that can be utilized in preclinical therapy trials in animal models of RTT and eventually within the context of clinical trials.

SUBMITTER: Dong HW

PROVIDER: S-EPMC7572861 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutation of the methyl-CpG-binding protein 2 (MECP2) gene. Although RTT has been associated with obesity, the underlying mechanism has not yet been elucidated. In this study, female heterozygous Mecp2-null mice (Mecp2+/- mice), a model of RTT, were fed a normal chow diet or high-fat diet (HFD), and the changes in molecular signaling pathways were investigated. Specifically, we examined the expression of genes related to the hypothalamus and dopamine reward circuitry, which represent a central network of feeding behavior control. In particular, dopamine reward circuitry has been shown to regulate hedonic feeding behavior, and its disruption is associated with HFD-related changes in palatability. The Mecp2+/- mice that were fed the normal chow showed normal body weight and food consumption, whereas those fed the HFD showed extreme obesity with hyperphagia, an increase of body fat mass, glucose intolerance, and insulin resistance compared with wild-type mice fed the HFD (WT-HFD mice). The main cause of obesity in Mecp2+/--HFD mice was a remarkable increase in calorie intake, with no difference in oxygen consumption or locomotor activity. Agouti-related peptide mRNA and protein levels were increased, whereas proopiomelanocortin mRNA and protein levels were reduced in Mecp2+/--HFD mice with hyperleptinemia, which play an essential role in appetite and satiety in the hypothalamus. The conditioned place preference test revealed that Mecp2+/- mice preferred the HFD. Tyrosine hydroxylase and dopamine transporter mRNA levels in the ventral tegmental area, and dopamine receptor and dopamine- and cAMP-regulated phosphoprotein mRNA levels in the nucleus accumbens were significantly lower in Mecp2+/--HFD mice than those of WT-HFD mice. Thus, HFD feeding induced dysregulation of food intake in the hypothalamus and dopamine reward circuitry, and accelerated the development of extreme obesity associated with addiction-like eating behavior in Mecp2+/- mice.

Project description:BackgroundRett syndrome (RTT), an X-linked neurodevelopmental rare disease mainly caused by MECP2-gene mutations, is a prototypic intellectual disability disorder. Reversibility of RTT-like phenotypes in an adult mouse model lacking the Mecp2-gene has given hope of treating the disease at any age. However, adult RTT patients still urge for new treatments. Given the relationship between RTT and monoamine deficiency, we investigated mirtazapine (MTZ), a noradrenergic and specific-serotonergic antidepressant, as a potential treatment.MethodsAdult heterozygous-Mecp2 (HET) female mice (6-months old) were treated for 30 days with 10 mg/kg MTZ and assessed for general health, motor skills, motor learning, and anxiety. Motor cortex, somatosensory cortex, and amygdala were analyzed for parvalbumin expression. Eighty RTT adult female patients harboring a pathogenic MECP2 mutation were randomly assigned to treatment to MTZ for insomnia and mood disorders (mean age = 23.1 ± 7.5 years, range = 16-47 years; mean MTZ-treatment duration = 1.64 ± 1.0 years, range = 0.08-5.0 years). Rett clinical severity scale (RCSS) and motor behavior assessment scale (MBAS) were retrospectively analyzed.ResultsIn HET mice, MTZ preserved motor learning from deterioration and normalized parvalbumin levels in the primary motor cortex. Moreover, MTZ rescued the aberrant open-arm preference behavior observed in HET mice in the elevated plus-maze (EPM) and normalized parvalbumin expression in the barrel cortex. Since whisker clipping also abolished the EPM-related phenotype, we propose it is due to sensory hypersensitivity. In patients, MTZ slowed disease progression or induced significant improvements for 10/16 MBAS-items of the M1 social behavior area: 4/7 items of the M2 oro-facial/respiratory area and 8/14 items of the M3 motor/physical signs area.ConclusionsThis study provides the first evidence that long-term treatment of adult female heterozygous Mecp2tm1.1Bird mice and adult Rett patients with the antidepressant mirtazapine is well tolerated and that it protects from disease progression and improves motor, sensory, and behavioral symptoms.

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Detection of neurophysiological features in female R255X MeCP2 mutation mice.

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