Fragile X mental retardation protein modulates somatic D-type K(+) channels and action potential threshold in the mouse prefrontal cortex

Axo-somatic K(+) channels control action potential output in part by acting in concert with voltage-gated Na(+) channels to set action potential threshold. Slowly inactivating, D-type K(+) channels are enriched at the axo-somatic region of cortical pyramidal neurons of the prefrontal cortex, where they regulate action potential firing. We previously demonstrated that D-type K(+) channels are downregulated in extratelencephalic-projecting (ET) L5 neurons in the medial prefrontal cortex (mPFC) of the Fmr1-knockout mouse model of fragile X syndrome (FX mice), resulting in a hyperpolarized action potential threshold. To test whether K(+) channel alterations are regulated in a cell-autonomous manner in FXS, we used a virus-mediated approach to restore expression of fragile X mental retardation protein (FMRP) in a small population of prefrontal neurons in male FX mice. Outside-out voltage-clamp recordings revealed a higher D-type K(+) conductance in FMRP-positive ET neurons compared with nearby FMRP-negative ET neurons. FMRP did not affect either rapidly inactivating A-type or noninactivating K(+) conductance. ET neuron patches recorded with FMRP(1–298), a truncated form of FMRP that lacks mRNA binding domains, included in the pipette solution had larger D-type K(+) conductance compared with heat-inactivated controls. Viral expression of FMRP in FX mice depolarized action potential threshold to near-wild-type levels in ET neurons. These results suggest that FMRP influences the excitability of ET neurons in the mPFC by regulating somatic D-type K(+) channels in a cell-autonomous, protein-protein-dependent manner. NEW & NOTEWORTHY We demonstrate that fragile X mental retardation protein (FMRP), which is absent in fragile X syndrome (FXS), regulates D-type potassium channels in prefrontal cortex L5 pyramidal neurons with subcerebral projections but not in neighboring pyramidal neurons without subcerebral projections. FMRP regulates D-type potassium channels in a protein-protein-dependent manner and rescues action potential threshold in a mouse model of FXS. These findings have implications for how changes in voltage-gated channels contribute to neurodevelopmental disorders.