Astrocytic GABA transport controls fidelity of temporal processing

Astrocytes control neural communications by influencing GABAergic transmission through uptake and synthesis of GABA. Impaired GABAergic signaling is thought to underlie cortical hyperexcitability in autism. Here we show that dysregulation of astrocyte GABA transport in Fragile X syndrome (FXS), a leading genetic cause of autism, contributes to circuit hyperexcitability. Human FXS astrocytes derived from patient-specific induced pluripotent stem cells and mouse Fmr1 knockout (KO) astrocytes display a significant increase in levels of GABA and GABA-synthesizing enzyme GAD65/67. Our astrocyte-specific Fmr1 KO (cKO) mouse model reveals reduced inhibitory connectivity and impaired cortical responses to sound. Reverse GABA transport in cortical astrocytes contributes to impaired fidelity of temporal processing and hyperactive behaviors in cKO mice. Blocking astrocyte GABA transport is sufficient to restore PV expression, cortical activity, EEG responses, and locomotor behavior. Our findings suggest astrocyte GABA transport plays a key role in regulating cortical inhibition, and contributes to autism-associated phenotypes. Highlights FXS astrocytes show elevated levels of GABA and its synthesizing enzyme GAD65/67 Fmr1 KO cortical astrocytes suppress PV expression leading to enhanced overall cell activity through reverse GABA transport Astrocyte-specific postnatal deletion of Fmr1 results in reduced inhibitory cortical connectivity, impaired fidelity of temporal processing and behavioral hyperactivity Acute blockade of astrocytic GABA transport is sufficient to restore cortical responses and correct hyperactive mouse behaviors Graphic Abstract