Elsevier

Neuroscience

Volume 103, Issue 4, 4 April 2001, Pages 1043-1050
Neuroscience

Fragile X mice develop sensory hyperreactivity to auditory stimuli

https://doi.org/10.1016/S0306-4522(01)00036-7Get rights and content

Abstract

Fragile X syndrome is the most prevalent cause of mental retardation. It is usually caused by the transcriptional inactivation of the FMR-1 gene. Although the cognitive defect is the most recognized symptom of fragile X syndrome, patients also show behavioral problems such as hyperarousal, hyperactivity, autism, aggression, anxiety and increased sensitivity to sensory stimuli. Here we investigated whether fragile X mice (fmr-1 gene knockout mice) exhibit abnormal sensitivity to sensory stimuli. First, hyperreactivity of fragile X mice to auditory stimulus was indicated in the prepulse inhibition paradigm. A moderately intense prepulse tone, that suppresses startle response to a strong auditory stimulus, elicited a significantly stronger effect in fragile X than in control mice. Second, sensory hyperreactivity of fragile X mice was demonstrated by a high seizure susceptibility to auditory stimulation. Selective induction of c-Fos, an early-immediate gene product, indicated that seizures involve auditory brainstem and thalamic nuclei. Audiogenic seizures were not due to a general increase in brain excitability because three different chemical convulsants (kainic acid, bicuculline and pentylenetetrazole) elicited similar effects in fragile X and wild-type mice.

These data are consistent with the increased responsiveness of fragile X patients to auditory stimuli. The auditory hypersensitivity suggests an abnormal processing in the auditory system of fragile X mice, which could provide a useful model to study the molecular and cellular changes underlying fragile X syndrome.

Section snippets

Animals

FMRP-KO mice1 on the FVB (FVB/NJ-Fmr1tm1Cgr) and mixed FVB/129 (FVB,129P-Fmr1tm1Cgr) background as well as FVB wild-type (WT) mice (FVB/NJ) were purchased from The Jackson Laboratory (Bar Harbor, ME). Male mice were used in all experiments because fragile X is an X-linked disorder and affects more males than females. All animal experiments were carried out according to the NIH animal care guidelines (NIH Publications No. 80-23). All efforts were made to minimize animal suffering and to use only

Increased prepulse inhibition of the acoustic startle response in fragile X mice

Prepulse inhibition of audiogenic startle is a phenomenon in which a weak prestimulus (prepulse) suppresses the response to a startle stimulus.9., 16., 19., 30., 36. Prepulse inhibition is mediated by a complex forebrain circuitry. As Fig. 1A shows, the baseline startle response was slightly lower (by 14%) in fragile X than in WT mice (KO mice: n=14; WT mice: n=16; P=0.0486; independent Student’s t-test). A more prominent difference was observed between the two genotypes in prepulse inhibition.

Increased behavioral responsiveness of fragile X mice to auditory stimulus

The major finding of this report is the hyperreactivity of fragile X mice to auditory stimuli. Abnormalities were detected in fragile X mice in prepulse inhibition and audiogenic seizure susceptibility.

Prepulse inhibition in fragile X mice, compared to control mice, was increased by 96 and 56% when 75 and 85 dB prestimulus was used, respectively. Prepulse inhibition of acoustic startle involves the activation of a forebrain gating circuitry that presumably allows prestimulus processing, while

Acknowledgements

This work was supported by grant R01NS34151 from the National Institute of Health to M.T.

References (43)

  • M Pieretti et al.

    Absence of expression of the FMR-1 gene in fragile X syndrome

    Cell

    (1991)
  • S Simler et al.

    C-fos expression after single and kindled audiogenic seizures in Wistar rats

    Neurosci. Lett.

    (1994)
  • G Sperk

    Kainic acid seizures in the rat

    Prog. Neurobiol.

    (1994)
  • A.J Verkerk et al.

    Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome

    Cell

    (1991)
  • J.F Willott et al.

    Abnormal tonotopic organization in the ventral cochlear nucleus of the hearing-impaired DBA/2 mouse

    Neurosci. Lett.

    (1982)
  • W.A Wilson et al.

    Common synaptic effects of pentylenetetrazol and penicillin

    Brain Res.

    (1974)
  • C.T Ashley et al.

    FMR1 protein: conserved RNP family domains and selective RNA binding

    Science

    (1993)
  • S Carlson et al.

    Caudal pontine reticular formation of C57BL/6J mice: responses to startle stimuli, inhibition by tones, and plasticity

    J. Neurophysiol.

    (1998)
  • M Davis

    Neural systems involved in fear-potentiated startle

    Ann. N.Y. Acad. Sci.

    (1989)
  • Fmr1 knockout mice: a model to study fragile X mental retardation

    Cell

    (1994)
  • D.E Eberhart et al.

    The fragile X mental retardation protein is a ribonucleoprotein containing both nuclear localization and nuclear export signals

    Hum. Molec. Genet.

    (1996)
  • Cited by (282)

    View all citing articles on Scopus
    View full text