FMRP regulates GABA_A receptor channel activity to control signal integration in hippocampal granule cells

Fragile X syndrome, the most common inherited form of intellectual disability, is caused by loss of fragile X mental retardation protein (FMRP). GABAergic system dysfunction is one of the hallmarks of FXS, yet the underlying mechanisms remain poorly understood. Here, we report that FMRP interacts with GABA_A receptor (GABA_AR) and modulates its single-channel activity. Specifically, FMRP regulates spontaneous GABA_AR opening through modulating its single-channel conductance and open probability in dentate granule cells. FMRP loss reduces spontaneous GABA_AR activity underlying tonic inhibition, while N-terminal FMRP fragment (aa 1–297) is sufficient to rapidly normalize tonic inhibition in Fmr1 knockout (KO) granule cells. FMRP-GABA_AR interaction is supported by co-immunoprecipitation of FMRP with at least one GABA_AR subunit, the α5. Functionally, FMRP-GABA_AR interaction ensures accuracy of coincidence detection of granule cells, which is markedly reduced in Fmr1 KOs. Our study reveals a mechanism underlying FMRP regulation of the GABAergic system and information processing in the hippocampus.