Altered integration of excitatory inputs onto the basal dendrites of layer 5 pyramidal neurons in a mouse model of Fragile X syndrome

Fragile X syndrome (FXS) is the most commonly known cause of autism spectrum disorders (ASD). We found that while control animals integrate subthreshold feedforward excitatory inputs linearly, this integration is sublinear in FXS mice, a defect that was reversed by genetic manipulation of BK channel activity. The sublinear integration contradicts what would be expected of sensory hypersensitivity classically associated with ASD. These findings instead support a model of FXS encompassing sensory hyposensitivity and predictive hypersensitivity at the level of cortical neurons. Moreover, these results highlight the need to study, in FXS and other forms of ASD, channelopathies in cortical feedforward and feedback pathways independently, their associations, and how cortical pyramidal neurons output is affected, which ultimately shapes behavior.