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

• Published in: Journal of medical genetics Vol. 46; no. 2; pp. 94 - 102
• Main Authors: Bilousova, T V, Dansie, L, Ngo, M, Aye, J, Charles, J R, Ethell, D W, Ethell, I M
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.02.2009; BMJ Publishing Group; BMJ Publishing Group LTD
• Subjects: Animals; Autism; Behavior, Animal - drug effects; Biological and medical sciences; Brain; Chromosome fragility (bloom syndrome, ataxia telangiectasia, fanconi anemia, x-linked mental retardation...); Dendritic Spines - drug effects; Dendritic Spines - metabolism; Disease Models, Animal; Drinking water; Fragile X Mental Retardation Protein - genetics; Fragile X Mental Retardation Protein - metabolism; Fragile X Syndrome - drug therapy; Fragile X Syndrome - genetics; Fragile X Syndrome - metabolism; Fundamental and applied biological sciences. Psychology; Gene Knockout Techniques; General aspects. Genetic counseling; Genetics of eukaryotes. Biological and molecular evolution; Hippocampus - enzymology; Hippocampus - metabolism; Intellectual disabilities; Matrix Metalloproteinase 9 - metabolism; Medical genetics; Medical sciences; Mice; Minocycline - pharmacology; Minocycline - therapeutic use; Molecular and cellular biology; Morphology; Motor Activity; Neurons; Proteins; United States > US; Performance evaluation; Human; Chromosome fragility; Animal model; Tetracycline derivatives; Rodentia; Vertebrata; Antibiotic; Mammalia; Mouse; Dendritic spine; Minocycline; Genetics; Protein synthesis inhibitor; Fragile X syndrome; Antibacterial agent; Performance
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.2008.061796

Background: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 (Fmr1 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.Methods:We evaluated the effects of minocycline on dendritic spine development in the hippocampus of young Fmr1 KO mice, and in primary cultures of hippocampal neurons isolated from those mice. Cognitive effects of minocycline in young WT and Fmr1 KO mice were also evaluated using established behavioural tests for general cognition, activity and anxiety.Results: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 Fmr1 KO mice. Minocycline treated Fmr1 KO mice show less anxiety in the elevated plus maze and more strategic exploratory behaviour in the Y maze as compared to untreated Fmr1 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 Fmr1 KO mice.Conclusion:These findings establish minocycline as a promising therapeutic for the treatment of fragile X mental retardation.