Cholesterol dysregulation in Rett syndrome: implications for synaptic function

Rett syndrome (RTT) is a progressive neurodevelopmental disorder mainly caused by mutations in the X-linked MECP2 gene. By affecting 1 in 10.000 live female births, it represents the main genetic cause of intellectual disability in girls worldwide [1]. Since MeCP2 is highly expressed in mature neurons, the majority of studies are focused on this cell type. However, besides neurons, astrocytes have been identified as active contributors to RTT pathogenesis as Mecp2 knock-out (KO) astrocytes fail to correctly support neuronal maturation and synaptogenesis [2]. Indeed, culturing wild-type (WT) neurons with KO astrocytes or treating them with KO astrocyte-conditioned medium (ACM) affects their synaptic phenotype [3]. Of note, one of the key synaptogenic factors released by astrocytes is cholesterol, which plays a crucial role in synapse formation and functioning. Several data highlight a defective cholesterol metabolism in RTT, supporting the hypothesis that abnormalities in astrocyte-produced cholesterol might contribute to synaptic dysfunctions. In this study, we report the deregulation of genes involved in cholesterol synthesis and secretion in primary KO astrocytes cultured alone or in co-culture with neurons and in MACS-sorted astrocytes. Moreover, we demonstrate that cholesterol supplementation completely rescues synaptic defects not only in WT neurons treated with KO ACM but also in Mecp2 heterozygous (HET) neurons, which better recapitulate the genetic pattern of RTT patients. Collectively, these data suggest cholesterol as a possible therapeutic target for synaptic dysfunctions in RTT with the perspective of validating the obtained results in animal models and human samples.