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Development of Structural and Functional Abnormalities Underlying Auditory Hypersensitivity in a Mouse Model of Fragile X Syndrome

  • Author(s): Wen, Teresa
  • Advisor(s): Razak, Khaleel A.
  • Ethell, Iryna M.
  • et al.
Abstract

Fragile X Syndrome (FXS) is a leading inherited cause of autism and intellectual disability. FXS occurs as a result Fmr1 gene hypermethylation, which leads to inactivation and loss of Fragile X Mental Retardation Protein (FMRP). Structural and functional studies of humans with FXS indicate auditory cortical deficits. Most notable is hypersensitivity to sounds. The Fmr1 knockout (KO) mouse is a well characterized animal model for FXS which also shows signs of auditory hypersensitivity, including increased acoustic startle and susceptibility to audiogenic seizures. In vivo electrophysiology data obtained from KO mouse primary auditory cortex (A1) indicate that neurons are hyperexcitable when presented with sounds and exhibit altered spectrotemporal processing. Fmr1 KO mice also exhibit EEG measures of abnormal network function, including baseline and stimulus-evoked cortical hyperexcitability. However, the developmental trajectory of these phenotypes has not been studied. Moreover, the molecular mechanisms underlying this altered excitatory/inhibitory balance are unknown. In this study, we characterized developmental changes in perineuronal net expression around GABAergic interneurons, neuronal response magnitudes, and network excitability in Fmr1 KO auditory cortex. In developing Fmr1 KO auditory cortex, there is a transient reduction in perineuronal net expression around GABAergic interneurons which coincides with single neuron hyperexcitability. In addition, there is increased oscillatory gamma during rest. These findings suggest that FXS is associated with developmental impairments in cortical processing. Future therapeutics may be more beneficial if administered during a developmental critical period.

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