Acute intermittent hypoxia-induced expression of brain-derived neurotrophic factor is disrupted in the brainstem of methyl-CpG-binding protein 2 null mice

Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding the transcription factor methyl-CpG-binding protein 2 (MeCP2). One of its targets is the gene encoding brain-derived neurotrophic factor (bdnf). In vitro studies using cultured neurons have produced conflicting results with respect to the role of MeCP2 in BDNF expression. Acute intermittent hypoxia (AIH) induces plasticity in the respiratory system characterized by long-term facilitation of phrenic nerve amplitude. This paradigm induces an increase in BDNF protein. We hypothesized that AIH leads to augmentation of BDNF transcription in respiratory-related areas of the brainstem and that MeCP2 is necessary for this process. Wild-type and mecp2 null (mecp2−/y) mice were subjected to three 5-min episodes of exposure to 8% O2/4% CO2/88% N2, delivered at 5-min intervals. Normoxia control wild-type and mecp2 null mice were exposed to room air for the total length of time, that is, 30 min. Following a recovery in room air, the pons and medulla were rapidly removed. Expression of BDNF protein and transcripts were determined by ELISA and quantitative PCR, respectively. AIH induced a significant increase in BDNF protein in the pons and medulla, and in mRNA transcript levels in the pons of wild-type animals. In contrast, there were no significant changes in either BDNF protein or transcripts in the pons or medulla of mice lacking MeCP2. The results indicate that MeCP2 is required for regulation of BDNF expression by acute intermittent hypoxia in vivo.

▶Previous in vivo studies with cultured neurons on the role of methyl-CpG-binding protein 2 (MeCP2) in upregulation of brain-derived neurotrophic factor (BDNF) have produced conflicting results. ▶Acute intermittent hypoxia has been shown to increase brainstem BDNF. ▶Here we show that in wild-type mice, acute intermittent hypoxia increases BDNF protein in pons and medulla and increases the bdnf protein coding transcript in pons. ▶In contrast, acute intermittent hypoxia in MeCP2 null littermates does not affect BDNF protein or transcript in either pons or medulla. ▶We conclude that MeCP2 is required for upregulation of brainstem BDNF following acute intermittent hypoxia.