Audiogenic Seizures in the<i>Fmr1</i>Knock-Out Mouse Are Induced by<i>Fmr1</i>Deletion in Subcortical, VGlut2-Expressing Excitatory Neurons and Require Deletion in the Inferior Colliculus

Abstract

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and the leading monogenetic cause of autism. One symptom of FXS and autism is sensory hypersensitivity (also called sensory over-responsivity). Perhaps related to this, the audiogenic seizure (AGS) is arguably the most robust behavioral phenotype in the FXS mouse model-the <i>Fmr1</i> knock-out (KO) mouse. Therefore, the AGS may be considered a mouse model of sensory hypersensitivity. Hyperactive circuits are hypothesized to underlie dysfunction in a number of brain regions in patients with FXS and <i>Fmr1</i> KO mice, and the AGS may be a result of this. But the specific cell types and brain regions underlying AGSs in the <i>Fmr1</i> KO are unknown. We used conditional deletion or expression of <i>Fmr1</i> in different cell populations to determine whether <i>Fmr1</i> deletion in those cells was sufficient or necessary, respectively, for the AGS phenotype in males. Our data indicate that <i>Fmr1</i> deletion in glutamatergic neurons that express vesicular glutamate transporter 2 (VGlut2) and are located in subcortical brain regions is sufficient and necessary to cause AGSs. Furthermore, the deletion of <i>Fmr1</i> in glutamatergic neurons of the inferior colliculus is necessary for AGSs. When we demonstrate necessity, we show that <i>Fmr1</i> expression in either the larger population of VGlut2-expressing glutamatergic neurons or the smaller population of inferior collicular glutamatergic neurons-in an otherwise <i>Fmr1</i> KO mouse-eliminates AGSs. Therefore, targeting these neuronal populations in FXS and autism may be part of a therapeutic strategy to alleviate sensory hypersensitivity.<b>SIGNIFICANCE STATEMENT</b> Sensory hypersensitivity in fragile X syndrome (FXS) and autism patients significantly interferes with quality of life. Audiogenic seizures (AGSs) are arguably the most robust behavioral phenotype in the FXS mouse model-the <i>Fmr1</i> knockout-and may be considered a model of sensory hypersensitivity in FXS. We provide the clearest and most precise genetic evidence to date for the cell types and brain regions involved in causing AGSs in the <i>Fmr1</i> knockout and, more broadly, for any mouse mutant. The expression of <i>Fmr1</i> in these same cell types in an otherwise <i>Fmr1</i> knockout eliminates AGSs indicating possible cellular targets for alleviating sensory hypersensitivity in FXS and other forms of autism.