Affordable Access

deepdyve-link
Publisher Website

Genetic reduction of MMP-9 in the Fmr1 KO mouse partially rescues prepulse inhibition of acoustic startle response.

Authors
  • Kokash, Jamiela1
  • Alderson, Erin M2
  • Reinhard, Sarah M2
  • Crawford, Cynthia A3
  • Binder, Devin K4
  • Ethell, Iryna M4
  • Razak, Khaleel A5
  • 1 Graduate Neuroscience Program, University of California, Riverside, United States. , (United States)
  • 2 Dept. of Psychology, University of California, Riverside, United States. , (United States)
  • 3 Psychology Dept. California State University, San Bernardino, United States. , (United States)
  • 4 Graduate Neuroscience Program, University of California, Riverside, United States; Biomedical Sciences Division, School of Medicine, University of California, Riverside, United States. , (United States)
  • 5 Graduate Neuroscience Program, University of California, Riverside, United States; Dept. of Psychology, University of California, Riverside, United States. Electronic address: [email protected] , (United States)
Type
Published Article
Journal
Brain research
Publication Date
May 22, 2019
Volume
1719
Pages
24–29
Identifiers
DOI: 10.1016/j.brainres.2019.05.029
PMID: 31128097
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Sensory processing abnormalities are consistently associated with autism, but the underlying mechanisms and treatment options are unclear. Fragile X Syndrome (FXS) is the leading known genetic cause of intellectual disabilities and autism. One debilitating symptom of FXS is hypersensitivity to sensory stimuli. Sensory hypersensitivity is seen in both humans with FXS and FXS mouse model, the Fmr1 knock out (Fmr1 KO) mouse. Abnormal sensorimotor gating may play a role in the hypersensitivity to sensory stimuli. Humans with FXS and Fmr1 KO mice show abnormalities in acoustic startle response (ASR) and prepulse inhibition (PPI) of startle, responses commonly used to quantify sensorimotor gating. Recent studies have suggested high levels of matrix metalloproteinase-9 (MMP-9) as a potential mechanism of sensory abnormalities in FXS. Here we tested the hypothesis that genetic reduction of MMP-9 in Fmr1 KO mice rescues ASR and PPI phenotypes in adult Fmr1 KO mice. We measured MMP-9 levels in the inferior colliculus (IC), an integral region of the PPI circuit, of WT and Fmr1 KO mice at P7, P12, P18, and P40. MMP-9 levels were higher in the IC of Fmr1 KO mice during early development (P7, P12), but not in adults. We compared ASR and PPI responses in young (P23-25) and adult (P50-80) Fmr1 KO mice to their age-matched wildtype (WT) controls. We found that both ASR and PPI were reduced in the young Fmr1 KO mice compared to age-matched WT mice. There was no genotype difference for ASR in the adult mice, but PPI was significantly reduced in the adult Fmr1 KO mice. The adult mouse data are similar to those observed in humans with FXS. Genetic reduction of MMP-9 in the Fmr1 KO mice resulted in a rescue of adult PPI responses to WT levels. Taken together, these results show sensorimotor gating abnormalities in Fmr1 KO mice, and suggest the potential for MMP-9 regulation as a therapeutic target to reduce sensory hypersensitivity. Copyright © 2019. Published by Elsevier B.V.

Report this publication

Statistics

Seen <100 times