Reversal of ultrasonic vocalization deficits in a mouse model of Fragile X Syndrome with minocycline treatment or genetic reduction of MMP-9.
Reversal of ultrasonic vocalization deficits in a mouse model of Fragile X Syndrome with minocycline treatment or genetic reduction of MMP-9.
复制标题
通过米诺环素治疗或 MMP-9 基因减少，逆转脆性 X 综合征小鼠模型的超声发声缺陷。
DOI：
10.1016/j.bbr.2019.112068
复制
发表时间：
2019
影响因子：
2.7
通讯作者：
Razak,KhaleelA
中科院分区：
文献类型：
--
作者：
Toledo,MaximilianoA;Wen,TeresaH;Binder,DevinK;Ethell,IrynaM;Razak,KhaleelA
Fragile X Syndrome (FXS) is a leading genetic cause of autism and intellectual disabilities. TheFmr1knockout (KO) mouse is a commonly studied pre-clinical model of FXS. Adult maleFmr1KO 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) andFmr1KO 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. UntreatedFmr1KO mice call at a significantly reduced rate compared to untreated WT mice. After minocycline treatment from 1 to 2 months of age, WT andFmr1KO 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 inFmr1KO mice which were heterozygous for MMP-9 (MMP-9+/−/Fmr1KO). The MMP-9+/−/Fmr1KO mice were between P75 and P90 at the time of recording. MMP-9+/−/Fmr1KO 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 inFmr1KO mice through attenuation of MMP-9 levels. These data suggest targeting MMP-9, even in late development, may reduce FXS symptoms.
