Abstract
Mutations in the X-linked gene encoding Methyl-CpG-binding protein 2 (MECP2) have been associated with neurodevelopmental and neuropsychiatric disorders including Rett Syndrome, X-linked mental retardation syndrome, severe neonatal encephalopathy, and Angelman syndrome. Although alterations in the performance of MeCP2-deficient mice in specific behavioral tasks have been documented, it remains unclear whether or not MeCP2 dysfunction affects patterns of periodic behavioral and electroencephalographic (EEG) activity. The aim of the current study was therefore to determine whether a deficiency in MeCP2 is sufficient to alter the normal daily rhythmic patterns of core body temperature, gross motor activity and cortical delta power. To address this, we monitored individual wild-type and MeCP2-deficient mice in their home cage environment via telemetric recording over 24 hour cycles. Our results show that the normal daily rhythmic behavioral patterning of cortical delta wave activity, core body temperature and mobility are disrupted in one-year old female MeCP2-deficient mice. Moreover, female MeCP2-deficient mice display diminished overall motor activity, lower average core body temperature, and significantly greater body temperature fluctuation than wild-type mice in their home-cage environment. Finally, we show that the epileptiform discharge activity in female MeCP2-deficient mice is more predominant during times of behavioral activity compared to inactivity. Collectively, these results indicate that MeCP2 deficiency is sufficient to disrupt the normal patterning of daily biological rhythmic activities.
Highlights
Mutations in the X-linked gene encoding Methyl-CPG-binding protein 2 (MECP2) cause the neurodevelopmental disorder Rett syndrome [1], and MECP2 mutations and duplications have been documented in several other neurodevelopmental and neuropsychiatric disorders, such as X-linked mental retardation syndrome, severe neonatal encephalopathy, Angelman’s syndrome, and in some cases of idiopathic autism [2,3,4]
The normal daily pattern of cyclic EEG delta wave activity is altered in Mecp22/+ mice
Mecp22/+ mice display spontaneous cortical epileptiform discharges, and this discharge activity is most pronounced when the mouse is in an active behavioral state
Summary
Mutations in the X-linked gene encoding Methyl-CPG-binding protein 2 (MECP2) cause the neurodevelopmental disorder Rett syndrome [1], and MECP2 mutations and duplications have been documented in several other neurodevelopmental and neuropsychiatric disorders, such as X-linked mental retardation syndrome, severe neonatal encephalopathy, Angelman’s syndrome, and in some cases of idiopathic autism [2,3,4]. To better elucidate how MeCP2 regulates neural development and neural function, and to allow for preclinical translational studies, several mutant mouse models have been developed that either lack MeCP2 or express a clinically relevant mutant form of MeCP2 [7,8,9,10,11] Studies in these mice have confirmed that MeCP2 deficiency alters normal brain development, synaptic communication, and neural network activities [12,13], and several behavioral impairments have been identified that likely stem from these neural deficiencies. Given the apparent link between impaired MeCP2 function and altered behavioral state rhythmicity in Rett syndrome patients [14] and in Mecp2308/y mice [15], we sought to determine whether impaired MeCP2 function would be sufficient to alter the daily
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