Reversal of ultrasonic vocalization deficits in a mouse model of Fragile X Syndrome with minocycline treatment or genetic reduction of MMP-9

Maximiliano A Toledo; Teresa H Wen; Devin K Binder; Iryna M Ethell; Khaleel A Razak

doi:10.1016/j.bbr.2019.112068

Reversal of ultrasonic vocalization deficits in a mouse model of Fragile X Syndrome with minocycline treatment or genetic reduction of MMP-9

Behav Brain Res. 2019 Oct 17:372:112068. doi: 10.1016/j.bbr.2019.112068. Epub 2019 Jul 2.

Authors

Maximiliano A Toledo¹, Teresa H Wen², Devin K Binder³, Iryna M Ethell³, Khaleel A Razak⁴

Affiliations

¹ Psychology Department, University of California, Riverside, CA, 92521, USA.
² Graduate Neuroscience Program, University of California, Riverside, CA, 92521, USA.
³ Graduate Neuroscience Program, University of California, Riverside, CA, 92521, USA; Biomedical Sciences, University of California, Riverside, CA, 92521, USA.
⁴ Psychology Department, University of California, Riverside, CA, 92521, USA; Graduate Neuroscience Program, University of California, Riverside, CA, 92521, USA. Electronic address: khaleel@ucr.edu.

Abstract

Fragile X Syndrome (FXS) is a leading genetic cause of autism and intellectual disabilities. The Fmr1 knockout (KO) mouse is a commonly studied pre-clinical model of FXS. Adult male Fmr1 KO mice produce fewer ultrasonic vocalizations (USVs) during mating, suggestive of abnormal social communication. Minocycline treatment for 2 months from birth alleviates a number of FXS phenotypes in mice, including USV call rate deficits. In the current study, we investigated if treatment initiated past the early developmental period would be effective, given that in many cases, individuals with FXS are treated during later developmental periods. Wildtype (WT) and Fmr1 KO mice were treated with minocycline between postnatal day (P) 30 and P58. Mating-related USVs were then recorded from these mice between P75 and P90 and analyzed for call rate, duration, bandwidth, and peak frequency. Untreated Fmr1 KO mice call at a significantly reduced rate compared to untreated WT mice. After minocycline treatment from 1 to 2 months of age, WT and Fmr1 KO mice exhibited similar call rates, due to an increase in calling in the latter group. Minocycline is thought to be effective in reducing FXS symptoms by lowering matrix-metalloproteinase-9 (MMP-9) levels. To determine whether abnormal MMP-9 levels underlie USV deficits, we characterized USVs in Fmr1 KO mice which were heterozygous for MMP-9 (MMP-9^+/-/Fmr1 KO). The MMP-9^+/-/Fmr1 KO mice were between P75 and P90 at the time of recording. MMP-9^+/-/Fmr1 KO mice exhibited significantly increased USV call rates, at times even exceeding WT rates. Taken together, these results suggest that minocycline may reverse USV call rate deficits in Fmr1 KO mice through attenuation of MMP-9 levels. These data suggest targeting MMP-9, even in late development, may reduce FXS symptoms.

Keywords: Autism; Fragile X Syndrome; MMP-9; Minocycline; Social communication; Ultrasonic vocalization.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animal Communication
Animals
Disease Models, Animal
Fragile X Mental Retardation Protein / genetics
Fragile X Mental Retardation Protein / metabolism
Fragile X Syndrome / drug therapy*
Fragile X Syndrome / genetics
Male
Matrix Metalloproteinase 9 / deficiency
Matrix Metalloproteinase 9 / genetics*
Matrix Metalloproteinase 9 / metabolism
Mice
Mice, Knockout
Minocycline / pharmacology*
Ultrasonics
Vocalization, Animal / drug effects*

Substances

Fmr1 protein, mouse
Fragile X Mental Retardation Protein
Matrix Metalloproteinase 9
Mmp9 protein, mouse
Minocycline

Grants and funding

U54 HD082008/HD/NICHD NIH HHS/United States