Stimulation of the brain serotonin receptor 7 rescues mitochondrial dysfunction in female mice from two models of Rett syndrome

Valenti, Daniela; Bari, Lidia de; Vigli, Daniele; Lacivita, Enza; Leopoldo, Marcello; Laviola, Giovanni; Vacca, Rosa Anna; Filippis, Bianca De

doi:10.1016/j.neuropharm.2017.04.024

Cited by 55 publications

(73 citation statements)

References 63 publications

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“…The 5-HT7R-mediated neurobehavioral and molecular changes were still present 2 months after the last injection, suggesting long-lasting beneficial effects on RTTrelated impairments. Subsequent studies uncovered functional alterations of brain mitochondria in RTT mouse models, that were rescued by chronic pharmacological stimulation of the 5-HT7R [98,99]. Similar promising preclinical results have been recently obtained in a mouse model of CDD, a rare neurodevelopmental syndrome characterized by severe neurobehavioral and motor deficits and stereotyped movements [100].…”

Section: The 5-ht7r and Neurological Diseasessupporting

confidence: 53%

Role of the Serotonin Receptor 7 in Brain Plasticity: From Development to Disease

Crispino

Volpicelli

Perrone-Capano

2019

Preprint

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Our knowledge on the plastic functions of the serotonin (5-HT) receptor subtype 7 (5-HT7R) in the brain physiology and pathology considerably advanced in the last few years. A wealth of data show that the 5-HT7R is a key player in the establishment and remodeling of neuronal cytoarchitecture during development and in the mature brain, and its dysfunction is linked to neuropsychiatric and neurodevelopmental diseases. The involvement of this receptor in synaptic plasticity is further demonstrated by data showing that its activation allows to rescue long term potentiation (LTP) and long term depression (LTD) deficits in various animal models of neurodevelopmental diseases. In addition, it is becoming clear that the 5-HT7R is involved in inflammatory intestinal diseases, possibly playing a role in the gut-brain axis, and modulates the function of immune cells. In this review, we will mainly focus on recent findings on this receptor’s role in the structural and synaptic plasticity of the mammalian brain, although we will also illustrate novel aspects highlighted in gut and immune system.

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Section: The 5-ht7r and Neurological Diseasessupporting

confidence: 53%

Role of the Serotonin Receptor 7 in Brain Plasticity: From Development to Disease

Crispino

Volpicelli

Perrone-Capano

2019

Preprint

View full text Add to dashboard Cite

show abstract

“…The 5-HT7R-mediated neurobehavioral and molecular changes were still present 2 months after the last injection, suggesting long-lasting, beneficial effects on RTT-related impairments. Subsequent studies uncovered functional alterations of brain mitochondria in RTT mouse models, that were rescued by the chronic pharmacological stimulation of the 5-HT7R [98,99]. Similar promising preclinical results have been recently obtained in a mouse model of CDD, a rare neurodevelopmental syndrome characterized by severe neurobehavioral and motor deficits and stereotyped movements [100].…”

Section: The 5-ht7r and Neurological Diseasessupporting

confidence: 53%

Role of the Serotonin Receptor 7 in Brain Plasticity: From Development to Disease

Crispino

Volpicelli

Perrone-Capano

2020

IJMS

View full text Add to dashboard Cite

Our knowledge on the plastic functions of the serotonin (5-HT) receptor subtype 7 (5-HT7R) in the brain physiology and pathology have advanced considerably in recent years. A wealth of data show that 5-HT7R is a key player in the establishment and remodeling of neuronal cytoarchitecture during development and in the mature brain, and its dysfunction is linked to neuropsychiatric and neurodevelopmental diseases. The involvement of this receptor in synaptic plasticity is further demonstrated by data showing that its activation allows the rescue of long-term potentiation (LTP) and long-term depression (LTD) deficits in various animal models of neurodevelopmental diseases. In addition, it is becoming clear that the 5-HT7R is involved in inflammatory intestinal diseases, modulates the function of immune cells, and is likely to play a role in the gut-brain axis. In this review, we will mainly focus on recent findings on this receptor’s role in the structural and synaptic plasticity of the mammalian brain, although we will also illustrate novel aspects highlighted in gastrointestinal (GI) tract and immune system.

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“…Also, brain ATP content is affected. Higher resting ATP levels with increased ATP turnover rates were reported for neonatal hippocampal Mecp2 -/y neurons (Toloe et al, 2014), whereas whole brain studies on adult symptomatic male and female Rett mice detected reduced ATP concentrations (Saywell et al, 2006; De Filippis et al, 2015; Valenti et al, 2017).…”

Section: Introductionmentioning

confidence: 90%

“…Indeed, Rett patients show lower expression levels of cytochrome c oxidase subunit I as well as reduced enzymatic activities of cytochrome c oxidase and succinate cytochrome c reductase (Coker and Melnyk, 1991; Gibson et al, 2010). Also in Rett mice, lowered enzymatic activities of the respiratory complexes are evident in brain and skeletal muscle (Kriaucionis et al, 2006; Gold et al, 2014; De Filippis et al, 2015; Valenti et al, 2017). In concert with altered O 2 consumption rates (Kriaucionis et al, 2006) these changes may easily culminate in reduced brain ATP contents (Saywell et al, 2006; De Filippis et al, 2015; Valenti et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Neuronal Redox-Imbalance in Rett Syndrome Affects Mitochondria as Well as Cytosol, and Is Accompanied by Intensified Mitochondrial O2 Consumption and ROS Release

et al. 2019

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Rett syndrome (RTT), an X chromosome-linked neurodevelopmental disorder affecting almost exclusively females, is associated with various mitochondrial alterations. Mitochondria are swollen, show altered respiratory rates, and their inner membrane is leaking protons. To advance the understanding of these disturbances and clarify their link to redox impairment and oxidative stress, we assessed mitochondrial respiration in defined brain regions and cardiac tissue of male wildtype (WT) and MeCP2-deficient ( Mecp2 -/y ) mice. Also, we quantified for the first time neuronal redox-balance with subcellular resolution in cytosol and mitochondrial matrix. Quantitative roGFP1 redox imaging revealed more oxidized conditions in the cytosol of Mecp2 -/y hippocampal neurons than in WT neurons. Furthermore, cytosol and mitochondria of Mecp2 -/y neurons showed exaggerated redox-responses to hypoxia and cell-endogenous reactive oxygen species (ROS) formation. Biochemical analyzes exclude disease-related increases in mitochondrial mass in Mecp2 -/y hippocampus and cortex. Protein levels of complex I core constituents were slightly lower in Mecp2 -/y hippocampus and cortex than in WT; those of complex V were lower in Mecp2 -/y cortex. Respiratory supercomplex-formation did not differ among genotypes. Yet, supplied with the complex II substrate succinate, mitochondria of Mecp2 -/y cortex and hippocampus consumed more O 2 than WT. Furthermore, mitochondria from Mecp2 -/y hippocampus and cortex mediated an enhanced oxidative burden. In conclusion, we further advanced the molecular understanding of mitochondrial dysfunction in RTT. Intensified mitochondrial O 2 consumption, increased mitochondrial ROS generation and disturbed redox balance in mitochondria and cytosol may represent a causal chain, which provokes dysregulated proteins, oxidative tissue damage, and contributes to neuronal network dysfunction in RTT.

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Stimulation of the brain serotonin receptor 7 rescues mitochondrial dysfunction in female mice from two models of Rett syndrome

Cited by 55 publications

References 63 publications

Role of the Serotonin Receptor 7 in Brain Plasticity: From Development to Disease

Role of the Serotonin Receptor 7 in Brain Plasticity: From Development to Disease

Role of the Serotonin Receptor 7 in Brain Plasticity: From Development to Disease

Neuronal Redox-Imbalance in Rett Syndrome Affects Mitochondria as Well as Cytosol, and Is Accompanied by Intensified Mitochondrial O2 Consumption and ROS Release

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