Interpreting the rich dialogue between astrocytes and neurons: An overview in Rett syndrome

Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily affecting females, with an incidence of 1 in 10,000 live births. It is caused mainly by de novo mutations in the X-linked MECP2 gene, which encodes methyl-CpG binding protein 2 (Mecp2), a key epigenetic regulator. MECP2 mutations have profound impacts on neurons, which exhibit morphological, synaptic and functional impairments. However, more recent evidence highlights a crucial role of astrocytes in RTT pathogenesis. Indeed, RTT astrocytes exhibit structural and functional impairments, failing to support neuronal growth and function through non-cell autonomous mechanisms. Studies reveal that MECP2 deficient astrocytes secrete abnormal factors that impair neuronal growth and synaptic function. Furthermore, they show dysregulated calcium signalling, disrupted glutamate and potassium homeostasis, and increased inflammatory responses, all of which contribute to neuronal dysfunction. Understanding these neuron-astrocyte interactions may offer novel therapeutic targets for RTT. In the review we aim at presenting the current knowledge of astrocyte-neuron crosstalk in RTT, describing the different mechanisms highlighted so far through which MECP2 mutant astrocytes impair neurons. Finally, we discuss existing and prospective methodological approaches for investigating cell-to-cell communication in RTT.