Astrocytes regulate inhibition in Fragile X Syndrome

Fragile X syndrome (FXS) is a leading genetic cause of autism-like symptoms that include sensory hypersensitivity and cortical hyperexcitability. Recent observations in humans and Fmr1 knockout (KO) animal models of FXS suggest abnormal GABAergic signaling. As most studies focused on neuron-centered mechanisms, astrocytes contribution to abnormal inhibition is largely unknown. Here we propose a non-neuronal mechanism of abnormal inhibitory circuit development in FXS. Astrocyte-specific deletion of Fmr1 during postnatal period leads to increased astrocytic GABA levels, but negatively impacts synaptic GABAA receptors and parvalbumin (PV) cell development. Developmental deletion of Fmr1 from astrocytes also affects communications between excitatory neurons and PV cells, impairing sound-evoked gamma synchronization in the cortex, while enhancing baseline and on-going sound-evoked EEG power, and leading to increased locomotor activity and altered social behaviors in adult mice. These results demonstrate a profound role of astrocytic FMRP in the development of inhibitory circuits and shaping normal inhibitory responses. ### Competing Interest Statement The authors have declared no competing interest.