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Ventilatory control in MECP2 knockout mice: effects of 7,8 dihydroxyflavone (7,8‐DHF)
Author(s) -
Johnson Rebecca Ann,
Lam Maxine,
Punzo Antonio,
Li Hongda,
Chang Qiang,
Mitchell Gordon
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1111.26
Subject(s) - rett syndrome , ventilation (architecture) , tropomyosin receptor kinase b , mecp2 , hypercapnia , medicine , brain derived neurotrophic factor , knockout mouse , endocrinology , anesthesia , neurotrophic factors , respiratory system , receptor , biology , mechanical engineering , biochemistry , gene , engineering , phenotype
Rett syndrome is a neurodevelopmental disorder associated with mutations in the MECP2 gene, reduced brain‐derived neurotrophic factor (BDNF) levels, and significant breathing abnormalities (e.g. prolonged central apneas). However, little is known concerning the time‐course of ventilatory impairment or if it can be pharmacologically improved. We tested the hypothesis that ventilatory capacity diminishes with age in the Mecp2 −/y mouse, a model for Rett syndrome. We further investigated the benefit of activating BDNF receptors (TrkB) by a recently identified TrkB agonist, 7,8‐DHF (80 mg/L in drinking water). Untreated mutants had frequent baseline apneas (2.6/min) and elevated tidal volumes (p<0.05). Mutants showed elevated hypoxic breathing frequencies and minute ventilation (11% O 2 ; p<0.05), but frequency decreased in hypercapnia (7.5% CO 2 ; p<0.05). Ventilation did not change with age (5–10 wks; p>0.05). In 2,7‐DHF treated mutant mice, baseline apneas were significantly reduced and hypoxic minute ventilation returned to near normal values (both p ≤ 0.05). Interestingly, hypercapnic ventilation was reduced in all mice by 7,8‐DHF (p<0.05). These novel findings suggest that: 1) ventilation remains stable between 5–10 wks of age in Mecp2 −/y mice, and 2) TrkB activation may attenuate breathing abnormalities. Thus, TrkB ligands may be of therapeutic benefit in Rett syndrome patients. Support: Internation Rett Syndrome Foundation and UW ICTR via NIH CTSA 1UL1RR025011