Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model

TLDR

Fragile X syndrome is the most common single‑gene cause of intellectual disability, marked by autistic‑like behaviors and dendritic spine maturation defects in patients and Fmr1 knockout mice. The study aimed to determine whether minocycline could promote dendritic spine maturation and improve behavioral outcomes in young Fmr1 knockout mice. Researchers treated hippocampal neurons and young Fmr1 KO mice with minocycline, assessing spine development in culture and in vivo, and evaluated cognition, activity, and anxiety through behavioral tests. Minocycline accelerated dendritic spine maturation, reduced anxiety, and enhanced exploratory behavior in Fmr1 KO mice, likely via inhibition of elevated MMP‑9 activity, supporting its potential as a therapeutic for fragile X.

Abstract

<h3>Background:</h3> Fragile X syndrome (FXS) is the most common single gene inherited form of mental retardation, with behaviours at the extreme of the autistic spectrum. Subjects with FXS and fragile X mental retardation gene knock out (<i>Fmr1</i> KO) mice, an animal model for FXS, have been shown to exhibit defects in dendritic spine maturation that may underlie cognitive and behavioural abnormalities in FXS. Minocycline is a tetracycline analogue that has been used in clinical trials for stroke, multiple sclerosis and several neurodegenerative conditions. <h3>Methods:</h3> We evaluated the effects of minocycline on dendritic spine development in the hippocampus of young <i>Fmr1</i> KO mice, and in primary cultures of hippocampal neurons isolated from those mice. Cognitive effects of minocycline in young WT and <i>Fmr1</i> KO mice were also evaluated using established behavioural tests for general cognition, activity and anxiety. <h3>Results:</h3> Our studies demonstrate that minocycline promotes dendritic spine maturation both in cultures and in vivo. The beneficial effects of minocycline on dendritic spine morphology are also accompanied by changes in the behavioural performance of 3-week-old <i>Fmr1</i> KO mice. Minocycline treated <i>Fmr1</i> KO mice show less anxiety in the elevated plus maze and more strategic exploratory behaviour in the Y maze as compared to untreated <i>Fmr1</i> KO mice. Our data suggest that these effects of minocycline may relate to its inhibitory action on MMP-9 expression and activity, which are higher in the hippocampus of <i>Fmr1</i> KO mice. <h3>Conclusion:</h3> These findings establish minocycline as a promising therapeutic for the treatment of fragile X mental retardation.