title: Acetyl-L-carnitine improves behavior and dendritic morphology in a mouse model of Rett syndrome.
abstract: Rett syndrome (RTT) is a devastating neurodevelopmental disorder affecting 1 in 10,000 girls. Approximately 90% of cases are caused by spontaneous mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). Girls with RTT suffer from severe motor, respiratory, cognitive and social abnormalities attributed to early deficits in synaptic connectivity which manifest in the adult as a myriad of physiological and anatomical abnormalities including, but not limited to, dimished dendritic complexity. Supplementation with acetyl-L-carnitine (ALC), an acetyl group donor, ameliorates motor and cognitive deficits in other disease models through a variety of mechanisms including altering patterns of histone acetylation resulting in changes in gene expression, and stimulating biosynthetic pathways such as acetylcholine. We hypothesized ALC treatment during critical periods in cortical development would promote normal synaptic maturation, and continuing treatment would improve behavioral deficits in the Mecp2(1lox) mouse model of RTT. In this study, wildtype and Mecp2(1lox) mutant mice received daily injections of ALC from birth until death (postnatal day 47). General health, motor, respiratory, and cognitive functions were assessed at several time points during symptom progression. ALC improved weight gain, grip strength, activity levels, prevented metabolic abnormalities and modestly improved cognitive function in Mecp2 null mice early in the course of treatment, but did not significantly improve motor or cognitive functions assessed later in life. ALC treatment from birth was associated with an almost complete rescue of hippocampal dendritic morphology abnormalities with no discernable side effects in the mutant mice. Therefore, ALC appears to be a promising therapeutic approach to treating early RTT symptoms and may be useful in combination with other therapies.
authors.affiliation: Department of Biology, Wellesley College, Wellesley, Massachusetts, United States of America. Laura.Schaevitz@tufts.edu
authors.forename: Laura R
authors.initials: LR
authors.lastname: Schaevitz
authors.forename: Raffaella
authors.initials: R
authors.lastname: Nicolai
authors.forename: Carla M
authors.initials: CM
authors.lastname: Lopez
authors.forename: Stefania
authors.initials: S
authors.lastname: D'Iddio
authors.forename: Emerenziana
authors.initials: E
authors.lastname: Iannoni
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Berger-Sweeney
mesh_terms: D000108:Acetylcarnitine / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D003712:Dendrites / Q000187:drug effects / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D006579:Heterozygote; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D020932:Nerve Growth Factor / Q000378:metabolism; D015518:Rett Syndrome / Q000097:blood / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D051783:Methyl-CpG-Binding Protein 2; D000108:Acetylcarnitine; D020932:Nerve Growth Factor