Reversing the Behavioral Phenotypes in fmr1 KO By the Reduction of Potassium Channel, Kv4.2

Background:  Fragile X syndrome (FXS) is a common form of mental disability and one of the known causes of autism. The mutation responsible for FXS is a large expansion of the trinucleotide CGG repeats that leads to DNA methylation of the fragile X mental retardation gene 1 (FMR1) and transcriptional silencing, resulting in the absence of fragile X mental retardation protein (FMRP), an mRNA binding protein. Although it is widely known that FMRP is critical for metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD), which has provided a general theme for developing pharmacological drugs for FXS, specific downstream targets of FMRP may also be of therapeutic value. We reported dendritic localization of mRNA of Kv4.2 voltage- gated potassium channel, which regulates synaptic plasticity, and its local translational regulation by FMRP. FMRP suppression of Kv4.2 is revealed by elevation of Kv4.2 in neurons from fmr1 KO mice. Moreover, treating hippocampal slices from fmr1 KO mice with Kv4 channel blocker restores long-term potentiation (LTP) induced by moderate stimuli. 

Objectives:  We reported dendritic localization of mRNA of Kv4.2 voltage- gated potassium channel, which regulates synaptic plasticity, and its local translational regulation by FMRP. FMRP suppression of Kv4.2 is revealed by elevation of Kv4.2 in neurons from fmr1 KO mice. Moreover, treating hippocampal slices from fmr1 KO mice with Kv4 channel blocker restores long-term potentiation (LTP) induced by moderate stimuli. 

Methods:  To test the effect of Kv4.2 levels in FXS, we generated fmr1 mutant mice with a 50 % reduction in Kv4.2 expression and studied a range of phenotypes with relevance to the human disorders. 

Results:  We found that Kv4.2 reduction in fmr1 KO mice reverses the altered repetitive and perseverative phenotype of fmr1 KO mice. We also found Kv4.2 reduction rescues the deficit in social behaviors. 

Conclusions:  Our results demonstrate that Kv4.2 contributes significantly to the pathogenesis of the disease, a finding that has significant therapeutic implications for FXS.