FMRP regulates GABA 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 receptor (GABAR) and modulates its single-channel activity. Specifically, FMRP regulates spontaneous GABAR opening through modulating its single-channel conductance and open probability in dentate granule cells. FMRP loss reduces spontaneous GABAR 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-GABAR interaction is supported by co-immunoprecipitation of FMRP with at least one GABAR subunit, the α5. Functionally, FMRP-GABAR 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.