Fragile X syndrome (FXS) is a heritable disease caused by mutations in the fragile X mental retardation 1 gene (FMR1) and carries a high risk for autism spectrum disorder (ASD), having an incidence of 1 in every 4,000 to 6,000 individuals. Currently, there are no effective treatments, and therefore, new treatments for FXS are urgently needed. The neuroanatomical phenotype that presents in adults with FXS, as well as in adult Fmr1 knockout (KO) mice, includes elevated dendritic spine density that resembles that seen in younger individuals. These findings suggest that synaptic pruning and maturation may be grossly impaired in FXS and further imply a role for the fragile X mental retardation protein (FMRP) in these processes. Despite our understanding of the unique role played by microglia in synaptic pruning during spine maturation in normal development, whether microglia-neuron communication contributes to the neuronal pathophysiology of FXS has yet to be determined.
Preliminary data from Hye Young Lee’s laboratory has demonstrated that microglia numbers may be severely decreased in Fmr1 KO mice. Conversely, there is an exaggerated response of Fmr1 KO microglia, as measured by the production of pro-inflammatory cytokines following an experimental neuroimmune stimulus. These data support the notion that microglia are deficient under basal conditions, in addition to being vulnerable to an external inflammatory stimulus in a mouse model of FXS. It’s also been shown that developmental regression can follow brain inflammation, suggesting a confounding role for the activation of the immune system in individuals with ASD more generally. As microglia are the resident immune cells within the brain, they are likely to play a key role in any altered basal neuroimmune environmental response, as well as in the exaggerated response to incoming inflammatory signals observed in ASD. Although previous studies have shown abnormal microglial activation and elevated cytokine levels in individuals with ASD1,2 these neuroimmune changes have not been extensively studied in FXS.
The central hypothesis of Lee’s current study is that microglial deficits contribute to the pathophysiology in FXS through altering bidirectional communication with neurons. This hypothesis is based on Lee’s preliminary studies demonstrating microglial deficits in Fmr1 KO mice both under basal conditions and neuroinflammatory conditions. To understand how microglial deficits contribute to FXS, Lee’s laboratory will assess the molecular mechanisms by which FMRP causes microglia dysfunction and will elucidate the effects of Fmr1 mutations on microglia-neuron communication and neuroinflammatory balance in the Fmr1 KO mouse model system. Given their preliminary work, Lee’s team expects to find that deficient microglia lead to increased spine density under basal conditions, but that neuroinflammatory conditions will cause microglia to become overstimulated and result in neuronal death.
The successful completion of the proposed work will increase our understanding of how FMRP expression in microglia contributes to normal neurophysiological function, the response to neuroinflammation and microglia-neuron interactions, as well as how disruption of these processes underlie the etiology of FXS. Further, increasing our understanding of the bidirectional functionality of microglia in Fmr1 KO mice will provide novel insights into potential targets for drug discovery for future treatments for FXS.