Fragile X syndrome is the most common single gene cause of inherited intellectual disability and autism and is associated with CNS hyperexcitability. Here, we demonstrate that the loss of the protein encoded by the Fmr1 gene, Fragile X messenger ribonucleoprotein (FMRP), alters dendritic signaling and excitability in cerebellar stellate cells (SC) in mice. In the cerebellum of Fmr1-/- knockout (Fmr1-/-) mice, SC have larger excitatory postsynaptic potentials (EPSP) following excitatory parallel fiber stimulation. We investigated the mechanism underpinning the enhanced EPSP peak amplitude and found diminished levels of A-type and TEA sensitive delayed rectifier potassium channel (Kdr) currents in Fmr1-/-. Using an established one-compartment Hodgkin-Huxley type model that captures key aspects of SC dynamics we find that attenuation in A-type, Kdr and calcium dependent potassium currents was unable to reproduce the experimentally observed increase in EPSP amplitude. In an expanded two-compartment Hodgkin Huxley type model we test the hypothesis that spatial decreases of potassium channels in different compartments of SCs contributes to increased EPSP amplitude in Fmr1-/- SCs. From this 2-compartment model, we predict that the reduction of dendritic Kdr is the key determinant of EPSP amplitude. The involvement of Kdrs in increased Fmr1-/- SC EPSP amplitude was validated experimentally through increased amplitude Fmr1-/- like EPSPs in WT SCs after TEA block of Kdrs. A heterogeneous population of 1000 two-compartment model SCs were then generated by sampling maximal current conductances
and synaptic input parameters from Gaussian distributions. The simulated firing and the variability in firing within this heterogenous population of SC models in response to synaptic input was increased after reduction of dendritic Kdr, demonstrating the role of dendritic Kdr in regulating excitability in cerebellar SCs and the contribution of decreased dendritic Kdr to hyperexcitability seen experimentally in Fmr1-/- SCs. Taken together, the disruption of translation independent FMRP modulation of dendritic delayed rectifiers in Fragile X syndrome is a key determinant in the dendrosomatic signalling of EPSPs and hyperexcitability in cerebellar SC.