Pathophysiology of Locus Ceruleus Neurons in a Mouse Model of Rett Syndrome

Taneja, Praveen; Ogier, Michaël; Brooks-Harris, Gabriel; Schmid, Danielle A.; Katz, David M.; Nelson, Sacha B.

doi:10.1523/jneurosci.3156-09.2009

Cited by 114 publications

(103 citation statements)

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“…Given the known abnormalities in adrenergic synthesis in RTT (10)(11)(12)(13)(14), we decided to test the effect on survival and behavior of chronic treatment with clenbuterol, a specific β2-adrenergic receptor agonist. In addition to its ability to effectively cross the bloodbrain barrier, clenbuterol can increase BDNF levels in the brain (28) and has been reported to improve cognition, mediate neuroprotection, and reduce neuroinflammation (29)(30)(31).…”

Section: Resultsmentioning

confidence: 99%

“…Female Mecp2 heterozygous mice display a delayed and more variable phenotype, but are important for determining the sex-specific effects and preclinical value of potential therapeutic interventions (7)(8)(9). Multiple studies have reported a plethora of physiological alterations in RTT patients and Mecp2 KO mice, including deficits in the modulation of adrenergic production and neurosecretion (10)(11)(12)(13)(14).…”

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confidence: 99%

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β2-Adrenergic receptor agonist ameliorates phenotypes and corrects microRNA-mediated IGF1 deficits in a mouse model of Rett syndrome

Mellios

Woodson

Garcia

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Rett syndrome is a severe childhood onset neurodevelopmental disorder caused by mutations in methyl-CpG-binding protein 2 (MECP2), with known disturbances in catecholamine synthesis. Here, we show that treatment with the β2-adrenergic receptor agonist clenbuterol increases survival, rescues abnormalities in respiratory function and social recognition, and improves motor coordination in young male Mecp2-null (Mecp2 −/y ) mice. Importantly, we demonstrate that short-term treatment with clenbuterol in older symptomatic female heterozygous (Mecp2 −/+ ) mice rescues respiratory, cognitive, and motor coordination deficits, and induces an anxiolytic effect. In addition, we reveal abnormalities in a microRNA-mediated pathway, downstream of brain-derived neurotrophic factor that affects insulin-like growth factor 1 (IGF1) expression in Mecp2 −/y mice, and show that treatment with clenbuterol restores the observed molecular alterations. Finally, cotreatment with clenbuterol and recombinant human IGF1 results in additional increases in survival in male null mice. Collectively, our data support a role for IGF1 and other growth factor deficits as an underlying mechanism of Rett syndrome and introduce β2-adrenergic receptor agonists as potential therapeutic agents for the treatment of the disorder.let-7f | LIN28A

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

β2-Adrenergic receptor agonist ameliorates phenotypes and corrects microRNA-mediated IGF1 deficits in a mouse model of Rett syndrome

Mellios

Woodson

Garcia

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Modulation of Neuronal Activity and Breathing-Experimental evidence suggests that LC neurons play an important role in brain stem CO 2 chemosensitivity and breathing regulation (9,33,61). Several groups of respiratory neurons and motoneurons are modulated by NE because NE augments cellular excitability via ␣ adrenoceptors (62,63).…”

Section: Discussionmentioning

confidence: 99%

“…In Mecp2-null mice, several groups of neurons, including LC neurons, are hyperexcitable (4,20,23,33), which appears to contribute to the breathing disorders in Mecp2-null mice. To test whether activation of the extrasynaptic GABA A Rs can alleviate the breathing abnormalities, we studied breathing activity using plethysmography in conscious Mecp2-null mice.…”

Section: F-h)mentioning

confidence: 99%

Methyl CpG Binding Protein 2 Gene Disruption Augments Tonic Currents of γ-Aminobutyric Acid Receptors in Locus Coeruleus Neurons

Zhong

Cui

Jin

et al. 2015

Journal of Biological Chemistry

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“…Previous studies have reported both cell-autonomous and non-autonomous effects of MeCP2 in murine models (34)(35)(36)(37). To address the role of MeCP2 in aminergic neurons, we selectively deleted MeCP2 in either TH-positive or PET1-positive neurons.…”

Section: Discussionmentioning

confidence: 99%

Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities

Samaco¹,

Mandel‐Brehm²,

Chao

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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214

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Rett syndrome (RTT) is characterized by specific motor, cognitive, and behavioral deficits. Because several of these abnormalities occur in other disease states associated with alterations in aminergic neurotransmitters, we investigated the contribution of such alterations to RTT pathogenesis. We found that both individuals with RTT and Mecp2-null mice have lower-than-normal levels of aminergic metabolites and content. Deleting Mecp2 from either TH-positive dopaminergic and noradrenergic neurons or PET1-positive serotonergic neurons in mice decreased corresponding neurotransmitter concentration and specific phenotypes, likely through MeCP2 regulation of rate-limiting enzymes involved in aminergic neurotransmitter production. These data support a cell-autonomous, MeCP2-dependent mechanism for the regulation of aminergic neurotransmitter synthesis contributing to unique behavioral phenotypes.dopamine ͉ norepinephrine ͉ Rett syndrome ͉ serotonin R ett syndrome (RTT, MIM 312750) is an X-linked neurodevelopmental disorder caused, in the vast majority of cases, by mutations in Methyl-CpG Binding Protein 2 (MECP2) (1). RTT primarily affects females, with a milder clinical phenotype correlating with late truncating and some missense mutations (2, 3). It has been suspected that aminergic neurons malfunction in RTT, because the heightened anxiety, aggression, and mood alterations seen in RTT and MECP2 disorders are associated with abnormalities of the serotonergic system in other human disorders (4-6). Rigidity and movement abnormalities are associated with dysfunction of dopaminergic system (7-9). Autonomic dysfunction underlying breathing irregularities could be attributable to decreased norepinephrine (7, 10). Although clinical studies have explored the hypothesis that the aminergic neurotransmitter systems might be altered in RTT, no solid conclusions have been reached. Early work suggested decreased aminergic metabolite levels in the spinal fluid of individuals with RTT (11, 12), but subsequent reports failed to identify such changes (13,14). More recently, one study reported instances of both decreased and increased aminergic metabolite levels in a few individuals with RTT (15). The interpretation of these clinical data are hindered by clinical heterogeneity, small sample sizes, and lack of a sufficient number of controls. To circumvent these problems, we explored the role of the aminergic neurotransmitter system by performing both clinical and animal studies. To determine whether the aminergic neurotransmitter system is altered in RTT, we analyzed the levels of the dopamine metabolite homovanillic acid (HVA) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in spinal fluid from women who both met the clinical criteria for RTT and had a diseasecausing MECP2 mutation. We also evaluated neurotransmitter changes in a RTT murine model and studied the neurochemical, molecular, and behavioral consequences of deleting Mecp2 from either TH-positive dopaminergic and noradrenergic neurons or PET1-positive serot...

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Pathophysiology of Locus Ceruleus Neurons in a Mouse Model of Rett Syndrome

Abstract: Rett syndrome (RTT) is a neurodevelopmental disorder caused by loss-of-function mutations in the Methyl

Cited by 114 publications

References 50 publications

β2-Adrenergic receptor agonist ameliorates phenotypes and corrects microRNA-mediated IGF1 deficits in a mouse model of Rett syndrome

β2-Adrenergic receptor agonist ameliorates phenotypes and corrects microRNA-mediated IGF1 deficits in a mouse model of Rett syndrome

Methyl CpG Binding Protein 2 Gene Disruption Augments Tonic Currents of γ-Aminobutyric Acid Receptors in Locus Coeruleus Neurons

Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities

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