Mechanisms underlying auditory processing deficits in Fragile X syndrome

• Published in: The FASEB journal 2020-03, Vol.34 (3), p.3501-3518
• Main Authors: McCullagh, Elizabeth A., Rotschafer, Sarah E., Auerbach, Benjamin D., Klug, Achim, Kaczmarek, Leonard K., Cramer, Karina S., Kulesza, Randy J., Razak, Khaleel A., Lovelace, Jonathan W., Lu, Yong, Koch, Ursula, Wang, Yuan
• Format: Article
• Language: English
• Subjects: Animals; Auditory Perception - physiology; auditory system; Autism Spectrum Disorder - metabolism; Autism Spectrum Disorder - physiopathology; autism spectrum disorders; circuit development; Fragile X syndrome; Fragile X Syndrome - metabolism; Fragile X Syndrome - physiopathology; Humans; hyperacusis; Models, Biological; synaptic transmission
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.201902435R

Autism spectrum disorders (ASD) are strongly associated with auditory hypersensitivity or hyperacusis (difficulty tolerating sounds). Fragile X syndrome (FXS), the most common monogenetic cause of ASD, has emerged as a powerful gateway for exploring underlying mechanisms of hyperacusis and auditory dysfunction in ASD. This review discusses examples of disruption of the auditory pathways in FXS at molecular, synaptic, and circuit levels in animal models as well as in FXS individuals. These examples highlight the involvement of multiple mechanisms, from aberrant synaptic development and ion channel deregulation of auditory brainstem circuits, to impaired neuronal plasticity and network hyperexcitability in the auditory cortex. Though a relatively new area of research, recent discoveries have increased interest in auditory dysfunction and mechanisms underlying hyperacusis in this disorder. This rapidly growing body of data has yielded novel research directions addressing critical questions regarding the timing and possible outcomes of human therapies for auditory dysfunction in ASD.