Work

Audiogenic Seizures in theFmr1Knock-Out Mouse Are Induced byFmr1Deletion in Subcortical, VGlut2-Expressing Excitatory Neurons and Require Deletion in the Inferior Colliculus

Year: 2019

Type: article

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—theFmr1knock-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 andFmr1KO mice, and the AGS may be a result of this. But the specific cell types and brain regions underlying AGSs in theFmr1KO are unknown. We used conditional deletion or expression ofFmr1in different cell populations to determine whetherFmr1deletion in those cells was sufficient or necessary, respectively, for the AGS phenotype in males. Our data indicate thatFmr1deletion 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 ofFmr1in glutamatergic neurons of the inferior colliculus is necessary for AGSs. When we demonstrate necessity, we show thatFmr1expression in either the larger population of VGlut2-expressing glutamatergic neurons or the smaller population of inferior collicular glutamatergic neurons—in an otherwiseFmr1KO mouse—eliminates AGSs. Therefore, targeting these neuronal populations in FXS and autism may be part of a therapeutic strategy to alleviate sensory hypersensitivity. SIGNIFICANCE STATEMENTSensory 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—theFmr1knockout—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 theFmr1knockout and, more broadly, for any mouse mutant. The expression ofFmr1in these same cell types in an otherwiseFmr1knockout eliminates AGSs indicating possible cellular targets for alleviating sensory hypersensitivity in FXS and other forms of autism.

Source: Journal of Neuroscience

DOI: 10.1523/jneurosci.0886-19.2019