%0 Journal Article %A Maham Rais %A Anna O. Kulinich %A Victoria Wagner %A Walker Woodard %A Xinghao S. Shuai %A Samantha N. Sutley %A Jamiela Kokash %A Timo P. Piepponen %A Maija Castren %A Khaleel A. Razak %A Iryna M. Ethell %T Astrocytes regulate inhibition in Fragile X Syndrome %D 2022 %R 10.1101/2022.02.08.479618 %J bioRxiv %P 2022.02.08.479618 %X Fragile X syndrome (FXS) is a leading genetic cause of autism-like symptoms associated with 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 defective inhibition is largely unknown. Here we show abnormally increased GABA levels in human FXS astrocytes derived from patient-specific induced pluripotent stem cells (iPSCs) and mouse astrocytes following astrocyte-specific Fmr1 KO during the postnatal period, affecting synaptic GABAA receptor levels and parvalbumin (PV) cell development. Developmental deletion of Fmr1 from astrocytes altered communication between excitatory neurons and PV cells, impairing cortical sound-evoked gamma synchronization, while enhancing baseline and on-going sound-evoked EEG power, and lead 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 StatementThe authors have declared no competing interest. %U https://www.biorxiv.org/content/biorxiv/early/2022/09/03/2022.02.08.479618.full.pdf