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 abnomalities 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 Mecp21lox mouse model of RTT. In this study, wildtype and Mecp21lox 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.
Highlights
Rett syndrome (RTT) is a devastating neurodevelopmental disorder characterized by a period of apparently normal development lasting 6 to 18 months, followed by a rapid loss of motor and verbal ability, mental retardation and respiratory abnormalities [1,2]
How altered expression of methyl-CpG-binding protein 2 (MeCP2) is translated into the myriad of neurochemical and neuroanatomical abnormalities that are reported in RTT remains unclear
Levels of carnitines are significantly elevated in wildtype and null ALC-treated mice
Summary
Rett syndrome (RTT) is a devastating neurodevelopmental disorder characterized by a period of apparently normal development lasting 6 to 18 months, followed by a rapid loss of motor and verbal ability, mental retardation and respiratory abnormalities [1,2]. RTT is frequently caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). How altered expression of MeCP2 is translated into the myriad of neurochemical and neuroanatomical abnormalities that are reported in RTT remains unclear. Neurochemical abnormalities include altered concentrations of glutamate/glutamine [5], acetylcholine [6], GABA [7], and other monoamine neurotransmitters [8]; while neuroanatomical abnormalities include reduced dendritic arborization [9] and decreased spine density in cortex and hippocampus [10]. Several mouse models of RTT have been created to facilitate an understanding of underlying molecular mechanisms, and provide an avenue to test preclinical therapies (reviewed in [11])
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