Reduced levels of brain-derived neurotrophic factor contribute to synaptic imbalance during the critical period of respiratory development in rats

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Abstract

Previously, our electrophysiological studies revealed a transient imbalance between suppressed excitation and enhanced inhibition in hypoglossal motoneurons of rats on postnatal days (P) 12–13, a critical period when abrupt neurochemical, metabolic, ventilatory and physiological changes occur in the respiratory system. The mechanism underlying the imbalance is poorly understood. We hypothesised that the imbalance was contributed by a reduced expression of brain-derived neurotrophic factor (BDNF), which normally enhances excitation and suppresses inhibition. We also hypothesised that exogenous BDNF would partially reverse this synaptic imbalance. Immunohistochemistry/single-neuron optical densitometry, real-time quantitative PCR (RT-qPCR) and whole-cell patch-clamp recordings were done on hypoglossal motoneurons in brainstem slices of rats during the first three postnatal weeks. Our results indicated that: (1) the levels of BDNF and its high-affinity tyrosine receptor kinase B (TrkB) receptor mRNAs and proteins were relatively high during the first 1–1.5 postnatal weeks, but dropped precipitously at P12–13 before rising again afterwards; (2) exogenous BDNF significantly increased the normally lowered frequency of spontaneous excitatory postsynaptic currents but decreased the normally heightened amplitude and frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) during the critical period; (3) exogenous BDNF also decreased the normally heightened frequency of miniature IPSCs at P12–13; and (4) the effect of exogenous BDNF was partially blocked by K252a, a TrkB receptor antagonist. Thus, our results are consistent with our hypothesis that BDNF and TrkB play an important role in the synaptic imbalance during the critical period. This may have significant implications for the mechanism underlying sudden infant death syndrome.

A critical window of respiratory development exists in rats around postnatal days 12 and 13, when an imbalance exists between suppressed excitation and heightened inhibition. We hypothesised that the underlying mechanism is a reduced expression of brain-derived neurotrophic factor (BDNF) and its TrkB receptors. Our data on hypoglossal nucleus are consistent with our hypothesis, and exogenous BDNF significantly increased the excitation and reduced the inhibition in single hypoglossal motoneurons analysed with patch-clamp recordings.

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