Since the discovery of the genetic mutation in Fragile X Syndrome (FXS) and the resulting absence of the fragile X messenger ribonucleoprotein (FMRP) much research has focused on the impact this has on neurons. Neuronal FMRP is primarily localized to the cytoplasm, dendrites, and postsynaptic dendritic spines, with minimal nuclear expression (Feng et al., 1997, Antar et al., 2005). However, FMRP is also found in non-neuronal cells of the brain during early development; specifically, those co-expressing markers denoting astrocyte and oligodendrocyte lineages (Pacey & Doering, 2007). Consistent with a role in brain development, expression of both neuronal and glial FMRP has been shown to peak during the period broadly associated with many processes like synaptogenesis, followed by an age-related reduction in expression (Pacey & Doering, 2007; Singh et al., 2007). FMRP is also upregulated in response to synaptic activity, as seen following sensory inputs to the rat somatosensory cortex (Todd & Mack, 2000), suggesting that this protein may be instrumental in activity-dependent synaptic modulation during these key periods. In this chapter, we discuss how the absence of FMRP affects glial cells and the impact this has on various neurodevelopmental processes in FXS. While we have focused on the role of astrocytes for our discussion, it is important to note that other glial populations, such as microglia and oligodendrocytes, also play essential roles in neurodevelopment and their potential for mitigating pathology in FXS are areas currently under investigation (reviewed in Andoh et al., 2019; Jeon et al., 2017).

Historically, research regarding the role of astrocytes has focused on their function as passive modulators of neuronal health, as they produce fuel for neuronal activity, manage neuronal waste, and interface with epithelial cells to form the blood–brain barrier (Kimelberg & Nedergaard, 2010). Importantly, recent studies have shown that the function of astrocytes extends far beyond solely supporting neurons, as they are highly involved in not only establishing synaptic connections, but also modulating processes such as neurogenesis, neuronal outgrowth, neuronal activity, and immune function within the central nervous system (Clarke & Barres, 2013). In addition to neuronal and epithelial communication, astrocytes widely interact with other glial cells through signalling factors or among themselves through the propagation of calcium waves, giving them broad influence within the CNS (Araque & Navarrete, 2010). Astrocyte-specific dysfunctions in FXS and ASD-related disorders continue to be uncovered, offering new insights into the cellular pathology of these disorders and potentially novel therapeutic targets. In the following sections, we review the cellular changes associated with FXS within the cortex and hippocampus, and then dissect the FXS pathologies across each developmental process and the affiliated astrocyte-mediated molecular mechanisms that underlie them.