Voltage-Independent SK Channel Dysfunction Causes Neuronal Hyperexcitability in the Hippocampus of Fmr1 KO mice.

Neuronal hyperexcitability is one of the major characteristics of Fragile X syndrome (FXS), yet the molecular mechanisms of this critical dysfunction remain poorly understood. Here we report a major role of voltage-independent K+ channel dysfunction in hyperexcitability of CA3 pyramidal neurons in Fmr1 KO mice. We observed a reduction of voltage-independent small conductance Ca2+ -activated K+ (SK) currents in both male and female mice leading to decreased AP threshold and reduced medium afterhyperpolarization (mAHP). These SK channel-dependent deficits led to markedly increased AP firing and abnormal input-output signal transmission of CA3 pyramidal neurons. The SK current defect was mediated, at least in part, by loss of FMRP interaction with the SK channels (specifically the SK2 isoform), without changes in the channel expression. Intracellular application of selective SK channel openers or a genetic reintroduction of an N-terminal FMRP fragment lacking the ability to associate with polyribosomes normalized all observed excitability defects in CA3 pyramidal neurons of Fmr1 KO mice. These results suggest that dysfunction of voltage-independent SK channels is the primary cause of CA3 neuronal hyperexcitability in Fmr1 KO mice and support the critical translation-independent role for FMRP as a regulator of neural excitability. Our findings may thus provide a new avenue to ameliorate hippocampal excitability defects in FXS. SIGNIFICANCE STATEMENT Despite two decades of research, no effective treatment is currently available for Fragile X syndrome (FXS). Neuronal hyperexcitability is widely considered as one of the hallmarks of FXS. Excitability research in the FXS field has thus far focused primarily on voltage-gated ion channels, while contributions from voltage-independent channels have been largely overlooked. Here we report that voltage-independent SK channel dysfunction causes hippocampal neuron hyperexcitability in the FXS mouse model. Our results support a major role for translation-independent FMRP function in regulating ion channel activity, and specifically the SK channels, in hyperexcitability defects in FXS. Our findings may thus open a new direction to ameliorate hippocampal excitability defects in FXS.