1. Ameliorating Auditory Hyperactivity and Improving Auditory Temporal Processing in a Mouse Model of Fragile X Syndrome by Targeting Serotonin-1A Post-Synaptic Receptors
- Author
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Tao, Xin, Razak, Khaleel1, Tao, Xin, Tao, Xin, Razak, Khaleel1, and Tao, Xin
- Abstract
Autism spectrum disorder (ASD) is a developmental disorder characterized by symptoms: intellectual difficulties, motor, and language impairment, altered sensory processing, social impediments, and repetitive behaviors. Only 10-20% ASD have clear genetic causes, and fragile X syndrome (FXS) is one of them. FXS is caused by a lack of fragile X messenger ribonucleoprotein (FMRP) whose expression is transcriptionally silenced due to Frm1 gene hypermethylation. Altered sensory processing across all domains has been widely described in humans with FXS. Most noticeable alterations in auditory processing are auditory hyperactivity and impaired temporal processing. The Fmr1 knockout (KO) mouse is a well characterized animal model for FXS studies which also shows signs of auditory hypersensitivity and impaired temporal processing: increased evoked and induced auditory responses, susceptible to audiogenic seizures (AGS), and reduced phase-locking to temporally modulated sound. The consistent manifestations of auditory hyperactivity and impaired temporal processing between human FXS individuals and Frm1 KO make it possible to evaluate potential FXS treatment with Frm1 KO mice. Previous studies by others implied enhancing serotonin signaling ameliorated auditory hyperactivity, yet they failed to pinpoint the specific serotonin receptor subtypes involved. With a more specific and highly selective post-synaptic serotonin-1A (5-HT1A) receptor agonist, NLX-101, we found the AGS susceptibility in developing Frm1 KO mice is significantly reduced, suggesting enhancing 5-HT1A signaling is effective in reducing auditory hyperactivity at the behavioral level in Frm1 KO mice. Electroencephalography (EEG) data acquired from Frm1 KO mice following NLX-101 treatment showed that enhancing 5-HT1A signaling not only reduced auditory hyperactivity at the network level but also improved temporal processing by increasing consistency of the auditory responses to temporally modulated stimuli. RNAscop
- Published
- 2024