Astrocyte-neuron interactions in Rett Syndrome and Fragile X Syndrome - PROJECT SUMMARY In typical neurodevelopment, astrocytes secrete factors to promote the establishment of healthy synapses and proper circuit function. In neurodevelopmental disorders, astrocyte protein secretion is aberrant with the potential to impact neuron morphology, synaptogenesis, and behavior. Rett Syndrome and Fragile X Syndrome are neurodevelopmental disorders with different genetic etiologies (loss-of-function mutation of MECP2 or FMR1, respectively) but have overlapping deficits in astrocyte function, neuronal activity, and behavior. While wildtype astrocytes typically support neuron outgrowth, astrocytes from Rett Syndrome or Fragile X Syndrome models inhibit neuron outgrowth, suggesting a non-cell autonomous effect through secreted factors. The identify of these factors is just beginning to be uncovered and how they impact synapse formation, neuron function, and behavior is largely unknown. To identify astrocyte secreted factors altered in neurodevelopmental disorders, the Allen lab recently profiled the protein ‘secretome’ of Rett, Fragile X, and Down Syndrome model astrocytes. Astrocyte secretion of the class 3 semaphorin, Sema3c, is increased in all three disorders suggesting a broader role in neurodevelopment. Class 3 semaphorins regulate axon guidance and synapse formation, elimination, and maintenance. This project tests the hypothesis that increased astrocyte Sema3c leads to neuronal and behavioral deficits in Rett Syndrome and Fragile X Syndrome and that reduction of astrocyte Sema3c will improve these deficits. Preliminary data indicates that astrocyte Sema3c is inhibitory to neurite outgrowth and that astrocyte-specific reduction of Sema3c improves visual acuity and anxiety-like behavior in Rett Syndrome. Aim 1 will test if astrocyte Sema3c reduction can improve synaptic activity and neuron morphology deficits observed in RTT and provide training in electrophysiological techniques. Aim 2 will identify the neuronal Sema3c receptor and test if reduction can also ameliorate neuronal and behavioral deficits. Aim 3 tests if astrocyte Sema3c reduction can also improve Fragile X Syndrome phenotypes. These experiments will inform on the role of astrocyte-neuron interactions in neurodevelopmental disorders and may indicate that increased astrocyte Sema3c is a convergent mechanism for nervous system dysregulation across Rett Syndrome and Fragile X Syndrome. This proposal may provide novel therapeutic targets for neurodevelopmental disorders, noting that inhibitors of Sema3c are currently being explored clinically for cancer treatments.
