# The Ca2+ Bridge: From Neurons to Circuits in Rett Syndrome

## TL;DR

This paper reviews how mutations in the Mecp2 gene lead to Rett syndrome by disrupting calcium signaling and affecting neuronal connectivity.

## Contribution

The paper highlights the novel crosstalk between Mecp2 and Ca2+ signaling in Rett syndrome pathophysiology.

## Key findings

- Mecp2 dysfunction disrupts Ca2+ regulation, contributing to Rett syndrome.
- Altered Ca2+ signaling affects Mecp2 function through post-translational modifications.
- Dysregulation of BDNF-miR132-Mecp2 axis and ryanodine receptors reduces structural plasticity in Rett syndrome.

## 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 (Ca2+) signaling as a central contributor to RTT pathophysiology. This review explores the link between Mecp2 and Ca2+ regulation by highlighting how Mecp2 affects Ca2+-dependent transcriptional pathways, while Ca2+ 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 Ca2+ homeostasis will provide critical insights into RTT pathogenesis and potential therapeutic targets aimed at restoring neuronal connectivity.