Mutations in the ( ) gene cause human intellectual disability, one of the most common cognitive disorders. However, the molecular mechanisms of -related intellectual disability remain poorly understood. We investigated the role of in synaptic function and animal behavior using male mouse and models. knock-out (KO) mice showed normal brain and spine morphology as well as intact synaptic plasticity; however, they also exhibited decreases in synaptic transmission and presynaptic release probability exclusively in excitatory synapses. Presynaptic function was impaired not only by loss of CRBN expression, but also by expression of pathogenic CRBN mutants (human R419X mutant and G552X mutant). We found that the BK channel blockers paxilline and iberiotoxin reversed this decrease in presynaptic release probability in KO mice. In addition, paxilline treatment also restored normal cognitive behavior in KO mice. These results strongly suggest that increased BK channel activity is the pathological mechanism of intellectual disability in mutations. ( ), a well known target of the immunomodulatory drug thalidomide, was originally identified as a gene that causes human intellectual disability when mutated. However, the molecular mechanisms of CRBN-related intellectual disability remain poorly understood. Based on the idea that synaptic abnormalities are the most common factor in cognitive dysfunction, we monitored the synaptic structure and function of knock-out (KO) animals to identify the molecular mechanisms of intellectual disability. Here, we found that KO animals showed cognitive deficits caused by enhanced BK channel activity and reduced presynaptic glutamate release. Our findings suggest a physiological pathomechanism of the intellectual disability-related gene and will contribute to the development of therapeutic strategies for -related intellectual disability.