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Neurobehavioral Alterations in a Genetic Murine Model of Feingold Syndrome 2.

ABSTRACT: Feingold syndrome (FS) is an autosomal dominant disorder characterized by microcephaly, short stature, digital anomalies, esophageal/duodenal atresia, facial dysmorphism, and various learning disabilities. Heterozygous deletion of the miR-17-92 cluster is responsible for a subset of FS (Feingold syndrome type 2, FS2), and the developmental abnormalities that characterize this disorder are partially recapitulated in mice that harbor a heterozygous deletion of this cluster (miR-17-92?/+ mice). Although Feingold patients develop a wide array of learning disabilities, no scientific description of learning/cognitive disabilities, intellectual deficiency, and brain alterations have been described in humans and animal models of FS2. The aim of this study was to draw a behavioral profile, during development and in adulthood, of miR-17-92?/+ mice, a genetic mouse model of FS2. Moreover, dopamine, norepinephrine and serotonin tissue levels in the medial prefrontal cortex (mpFC), and Hippocampus (Hip) of miR-17-92?/+ mice were analyzed.Our data showed decreased body growth and reduced vocalization during development. Moreover, selective deficits in spatial ability, social novelty recognition and memory span were evident in adult miR-17-92?/+ mice compared with healthy controls (WT). Finally, we found altered dopamine as well as serotonin tissue levels, in the mpFC and Hip, respectively, of miR-17-92?/+ in comparison with WT mice, thus suggesting a possible link between cognitive deficits and altered brain neurotransmission.

SUBMITTER: Fiori E

PROVIDER: S-EPMC4561592 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Neurobehavioral Alterations in a Genetic Murine Model of Feingold Syndrome 2.

Fiori E E Babicola L L Andolina D D Coassin A A Pascucci T T Patella L L Han Y-C YC Ventura A A Ventura R R

Behavior genetics 20150531 5

Feingold syndrome (FS) is an autosomal dominant disorder characterized by microcephaly, short stature, digital anomalies, esophageal/duodenal atresia, facial dysmorphism, and various learning disabilities. Heterozygous deletion of the miR-17-92 cluster is responsible for a subset of FS (Feingold syndrome type 2, FS2), and the developmental abnormalities that characterize this disorder are partially recapitulated in mice that harbor a heterozygous deletion of this cluster (miR-17-92∆/+ mice). Alt ...[more]

PMID: 26026879

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Project description:Fragile X syndrome (FXS), a disorder of synaptic development and function, is the most prevalent genetic form of intellectual disability and autism spectrum disorder. FXS mouse models display clinically-relevant phenotypes, such as increased anxiety and hyperactivity. Despite their availability, so far advances in drug development have not yielded new treatments. Therefore, testing novel drugs that can ameliorate FXS' cognitive and behavioral impairments is imperative. ANAVEX2-73 (blarcamesine) is a sigma-1 receptor (S1R) agonist with a strong safety record and preliminary efficacy evidence in patients with Alzheimer's disease and Rett syndrome, other synaptic neurodegenerative and neurodevelopmental disorders. S1R's role in calcium homeostasis and mitochondrial function, cellular functions related to synaptic function, makes blarcamesine a potential drug candidate for FXS. Administration of blarcamesine in 2-month-old FXS and wild type mice for 2 weeks led to normalization in two key neurobehavioral phenotypes: open field test (hyperactivity) and contextual fear conditioning (associative learning). Furthermore, there was improvement in marble-burying (anxiety, perseverative behavior). It also restored levels of BDNF, a converging point of many synaptic regulators, in the hippocampus. Positron emission tomography (PET) and ex vivo autoradiographic studies, using the highly selective S1R PET ligand [18F]FTC-146, demonstrated the drug's dose-dependent receptor occupancy. Subsequent analyses also showed a wide but variable brain regional distribution of S1Rs, which was preserved in FXS mice. Altogether, these neurobehavioral, biochemical, and imaging data demonstrates doses that yield measurable receptor occupancy are effective for improving the synaptic and behavioral phenotype in FXS mice. The present findings support the viability of S1R as a therapeutic target in FXS, and the clinical potential of blarcamesine in FXS and other neurodevelopmental disorders.

Project description:IntroductionCoxsackievirus B3 (CVB3) is known to induce acute and chronic myocarditis. Most infections are clinically unapparent but some patients suffer from ventricular arrhythmias (VA) and sudden cardiac death (SCD). Studies showed that acute CVB3 infection may cause impaired function of cardiac ion channels, creating a proarrhythmic substrate. However, it is unknown whether low level CVB3+ expression in myocytes may cause altered cardiac electrophysiology leading to VA.MethodsCellular electrophysiology was used to analyze cellular action potentials (APs) and occurrence of afterdepolarizations from isolated cardiomyocytes of wildtype (WT) and transgenic CVB3ΔVP0 (CVB3+) mice. Further, we studied surface ECGs, monophasic APs, ventricular effective refractory period (VERP) and inducibility of VAs in Langendorff-perfused whole hearts. All used cardiomyocytes and whole hearts originated from male mice.ResultsCellular action potential duration (APD) in WT and CVB3+ myocytes was unchanged. No difference in mean occurrence or amplitude of afterdepolarizations in WT and CVB3+ myocytes was found. Interestingly, resting membrane potential in CVB3+ myocytes was significantly hyperpolarized (WT: -90.0±2.2 mV, n = 7; CVB3+: -114.1±3.0 mV, n = 14; p<0.005). Consistently, in Langendorff-perfused hearts, APDs were also not different between WT and CVB3+ whole hearts. Within both groups, we found a heart rate dependent shortening of ADP90 with increasing heart rate in Langendorff-perfused hearts. VERP was significantly prolonged in CVB3+ hearts compared to WT (WT: 36.0±2.7 ms, n = 5; CVB3+: 47.0±2.0 ms, n = 7; p = 0.018). Resting heart rate (HR) in Langendorff-perfused hearts was not significantly different between both genotypes. Electrical pacing protocols induced no VA in WT and CVB3+ hearts.ConclusionIn CVB3+ mice, prolonged ventricular refractoriness and hyperpolarized resting membrane potentials in presence of unchanged APD were observed, suggesting that low level CVB3 expression does not promote VA by altered cardiac electrophysiology in this type of chronic myocarditis. These findings may suggest that other mechanisms such as chronic myocardial inflammation or fibrosis may account for arrhythmias observed in patients with chronic enteroviral myocarditis.

Dataset Information

Neurobehavioral Alterations in a Genetic Murine Model of Feingold Syndrome 2.

Publications

Neurobehavioral Alterations in a Genetic Murine Model of Feingold Syndrome 2.

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