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Dysfunction of Circadian System in a Mouse Model of Rett Syndrome

  • Author(s): Li, Quan
  • Advisor(s): Colwell, Christopher S
  • Sun, Yi E
  • et al.
Abstract

Rett Syndrome (RTT) is a severe X-chromosome-linked neurological disorder and worldwide represents the second leading genetic cause of intellectual disabilities in females. The majority of RTT cases are caused by the mutations in MECP2 gene encoding methyl-CpG-binding protein 2 (MECP2) and sleep disturbances with abnormal sleep/wake cycles are prevalent in RTT patients indicating a deficit in their circadian timing system.

Hemizygous Mecp2-/y mice were examined to determine the disruption of circadian system and the potential underlying mechanisms caused by MeCP2 dysfunction. Mecp2-/y mice exhibited severe deficits in circadian rhythms of locomotor activity and temporal pattern of daily activity combined with extremely fragmented sleep behavior. Moreover, spontaneous electrical activity and molecular core clock components were significantly attenuated within the SCN

suggesting the weakened central clockwork. Peripheral organs also showed disrupted molecular core clock expression suggesting the disorganized peripheral oscillators. ChIP-qPCR study using Mecp2-/yMEFs revealed a loss of rhythmic binding pattern of histone markers at the clock gene promoter regions due to the loss of MeCP2. In addition, RTT individual fibroblasts exhibited abnormal core clock gene expression and Mecp2-/y mice were vulnerable due to the destabilized circadian system causing a shortened lifespan. These data strongly indicated an essential role of MeCP2 in circadian timing system and revealed the importance of stabilization of circadian system and sleep/wake cycles during the clinical care of RTT individuals.

Currently there is no cure for RTT patients. A small molecule, 7,8-Dihydroxyflavone (7,8-DHF) was recently identified to be a potent TrkB receptor agonist that mimicked BDNF functions as a potential therapeutic intervention for RTT treatment. Systematic administration

of 7,8-DHF activated the phosphorylation of TrkB receptors and generated robust downstream Akt phorphorylation in wild-type mouse cortex and hippocampus tissues. Although systematic administration of 7,8-DHF did not significantly rescue the life span of the Mecp2-/y mutants, incubation of cortical slices with 7,8-DHF in vitro significantly increased the spontaneous firing rate of L5 pyramidal neurons of Mecp2-/ymutant mice. Taken together, these data suggested that 7,8-DHF rescued the physiological defect caused by the absence of MeCP2 and raised the possibility that it could be therapeutically useful for RTT treatment.

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