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The Ca 2+ Bridge: From Neurons to Circuits in Rett Syndrome.

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Title: The Ca 2+ Bridge: From Neurons to Circuits in Rett Syndrome.
Authors: Molina Calistro L; Facultad de Ciencias, Universidad San Sebastián, Lago Panguipulli 1390, Puerto Montt 5501842, Chile., Arancibia Y; Facultad de Ciencias, Universidad San Sebastián, Lago Panguipulli 1390, Puerto Montt 5501842, Chile.; Millennium Nucleus of Neuroepigenetics and Plasticity (EpiNeuro), Santiago 8320000, Chile., Alarcón J; Facultad de Medicina, Universidad San Sebastián, Lago Panguipulli 1390, Puerto Montt 5501842, Chile., Torres RF; Facultad de Ciencias, Universidad San Sebastián, Lago Panguipulli 1390, Puerto Montt 5501842, Chile.
Source: International journal of molecular sciences [Int J Mol Sci] 2025 Oct 29; Vol. 26 (21). Date of Electronic Publication: 2025 Oct 29.
Publication Type: Journal Article; Review
Language: English
Journal Info: Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
Imprint Name(s): Original Publication: Basel, Switzerland : MDPI, [2000-
MeSH Terms: Rett Syndrome*/metabolism , Rett Syndrome*/genetics , Rett Syndrome*/pathology , Neurons*/metabolism , Neurons*/pathology , Calcium*/metabolism , Calcium Signaling*, Humans ; Methyl-CpG-Binding Protein 2/metabolism ; Methyl-CpG-Binding Protein 2/genetics ; Animals ; Brain-Derived Neurotrophic Factor/metabolism ; Ryanodine Receptor Calcium Release Channel/metabolism ; MicroRNAs/metabolism ; MicroRNAs/genetics ; Mutation
Abstract: Rett syndrome (RTT) is a severe neurodevelopmental disorder caused primarily by mutations in the gene encoding the methyl-CpG-binding protein 2 (Mecp2). Mecp2 binds to methylated cytosines, playing a crucial role in chromatin organization and transcriptional regulation. At the neurobiological level, RTT is characterized by dendritic spine dysgenesis and altered excitation-inhibition balance, drawing attention to the mechanisms that scale from mutations in a nuclear protein to altered neuronal connectivity. Although Mecp2 dysfunction disrupts multiple neuronal processes, emerging evidence highlights altered calcium (Ca 2+ ) signaling as a central contributor to RTT pathophysiology. This review explores the link between Mecp2 and Ca 2+ regulation by highlighting how Mecp2 affects Ca 2+ -dependent transcriptional pathways, while Ca 2+ modulates Mecp2 function by inducing post-translational modifications. We discuss this crosstalk in light of evidence from RTT models, with a particular focus on the brain-derived neurotrophic factor BDNF-miR132-Mecp2 axis and the dysregulation of ryanodine receptors (RyRs). Additionally, we examine how these perturbations contribute to the reduced structural plasticity and the altered activity-driven gene expression that characterizes RTT. Understanding the intersection between Mecp2 function and Ca 2+ homeostasis will provide critical insights into RTT pathogenesis and potential therapeutic targets aimed at restoring neuronal connectivity.
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Grant Information: 11230898 Agencia Nacional de Investigación y Desarrollo; 11240855 Agencia Nacional de Investigación y Desarrollo; 3200655 Agencia Nacional de Investigación y Desarrollo; NCN2023_032 ANID-MILENIO
Contributed Indexing: Keywords: Mecp2; Rett syndrome; calcium; calcium signaling; neuronal function and dysfunction; ryanodine receptors
Substance Nomenclature: 0 (Methyl-CpG-Binding Protein 2)
SY7Q814VUP (Calcium)
0 (Brain-Derived Neurotrophic Factor)
0 (MECP2 protein, human)
0 (Ryanodine Receptor Calcium Release Channel)
0 (MicroRNAs)
Entry Date(s): Date Created: 20251113 Date Completed: 20251113 Latest Revision: 20251116
Update Code: 20251116
PubMed Central ID: PMC12609203
DOI: 10.3390/ijms262110490
PMID: 41226529
Database: MEDLINE
Description
Abstract:Rett syndrome (RTT) is a severe neurodevelopmental disorder caused primarily by mutations in the gene encoding the methyl-CpG-binding protein 2 (Mecp2). Mecp2 binds to methylated cytosines, playing a crucial role in chromatin organization and transcriptional regulation. At the neurobiological level, RTT is characterized by dendritic spine dysgenesis and altered excitation-inhibition balance, drawing attention to the mechanisms that scale from mutations in a nuclear protein to altered neuronal connectivity. Although Mecp2 dysfunction disrupts multiple neuronal processes, emerging evidence highlights altered calcium (Ca <sup>2+</sup> ) signaling as a central contributor to RTT pathophysiology. This review explores the link between Mecp2 and Ca <sup>2+</sup> regulation by highlighting how Mecp2 affects Ca <sup>2+</sup> -dependent transcriptional pathways, while Ca <sup>2+</sup> modulates Mecp2 function by inducing post-translational modifications. We discuss this crosstalk in light of evidence from RTT models, with a particular focus on the brain-derived neurotrophic factor BDNF-miR132-Mecp2 axis and the dysregulation of ryanodine receptors (RyRs). Additionally, we examine how these perturbations contribute to the reduced structural plasticity and the altered activity-driven gene expression that characterizes RTT. Understanding the intersection between Mecp2 function and Ca <sup>2+</sup> homeostasis will provide critical insights into RTT pathogenesis and potential therapeutic targets aimed at restoring neuronal connectivity.
ISSN:1422-0067
DOI:10.3390/ijms262110490