FMRP regulates GABAA 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(A)R) and modulates its single-channel activity. Specifically, FMRP regulates spontaneous GABA(A)R opening through modulating its single-channel conductance and open probability in dentate granule cells. FMRP loss reduces spontaneous GABAAR 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(A)R interaction is supported by co-immunoprecipitation of FMRP with at least one GABA(A)R subunit, the a5. Functionally, FMRP-GABA(A)R interaction ensures accuracy of coincidence detection of granule cells, which is markedly reduced in Fmr1 KOs. Our study reveals a mechanismunderlying FMRP regulation of the GABAergic system and information processing in the hippocampus.