BRAIN-DERIVED NEUROTROPHIC FACTOR IS REQUIRED FOR NORMAL DEVELOPMENT OF THE CENTRAL RESPIRATORY RHYTHM IN MICE

1. Molecular mechanisms underlying maturation of the central respirato ry rhythm are largely unknown. Previously, we found that brain-derived neurotrophic factor (BDNF) is required for expression of normal breat hing behaviour in newborn mice, raising the possibility that maturatio n of central respiratory output is dependent on BDNF. 2. Respiratory a ctivity was recorded in vitro from cervical ventral roots (C1 or C4) u sing the isolated brainstem-spinal cord preparation from postnatal day (P) 0.5-2.0 and P4.5 wildtype mice and mice lacking functional bdnf a lleles. 3. Loss of one or both bdnf alleles resulted in an approximate ly 50% depression of central respiratory frequency compared with wild- type controls. In addition, respiratory cycle length variability was 2 14% higher in bdnf null(bdnf(-/-)) animals compared with controls at P 4.5. In contrast, respiratory burst duration was unaffected by bdnf ge ne mutation. 4. These derangements of central respiratory rhythm paral leled the ventilatory depression and irregular breathing characteristi c of bdnf mutants in vivo, indicating that central deficits can largel y account for the abnormalities in resting ventilation produced by gen etic loss of BDNF. BDNF is thus the first growth factor identified tha t is required for normal development of the central respiratory rhythm , including the stabilization of central respiratory output that occur s after birth.