Hippocampal Astrocytes Impact Postnatal Development of Inhibitory Connections, Parvalbumin Levels, Social, and Spatial Navigation Behaviors in a Mouse Model of Fragile X Syndrome.

Fragile X Syndrome (FXS) is a leading genetic cause of autism-like symptoms and intellectual disability, resulting from epigenetic silencing of the Fragile X messenger ribonucleoprotein (Fmr1) gene. Recent observations in FXS models suggest abnormal GABAergic signaling and excitation/inhibition imbalance may underlie the pathophysiology of FXS. As most studies have focused on neuronal mechanisms, the role of astrocytes in mediating defective inhibition in FXS is largely unknown. Our previous study showed the effects of astrocyte-specific Fmr1 conditional knockout (cKO) on cortical inhibitory circuit development using EEGs that were attributed to excess GABA synthesis by Fmr1 KO astrocytes. As the hippocampus plays an important role in spatial learning and social behaviors that are altered in FXS, in this study we focused on dissecting the mechanism of abnormal inhibition in the CA1 hippocampus using slice electrophysiology. While we observed a reduction in the expression of synaptic GABAA receptor subunits and overall density of perisomatic GABAergic synapses in cKO, the amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) was enhanced in pyramidal cells. In contrast to changes in phasic inhibition, astrocyte-specific cKO did not affect tonic inhibition in pyramidal cells or the expression of extrasynaptic GABAA receptors, which were both impaired in global KO. Our study suggests that elevated levels of extracellular GABA due to abnormal GABA transport in cKO astrocytes may contribute to the enhanced power of sIPSCs and potentially affect parvalbumin (PV) cell activity. Acute inhibition of GABA transport in astrocytes enhanced PV expression and improved spatial memory and socialization in cKO mice. Our work supports astrocytes as key players in the development and regulation of hippocampal inhibitory circuits in FXS, potentially through GABA transport.