Abstract
Nicotine exposure during the fetal and neonatal periods (Developmental nicotine exposure, DNE) is associated with ineffective upper airway protective reflexes in infants. This could be explained by desensitized chemoreceptors and/or mechanoreceptors, diminished neuromuscular transmission or altered synaptic transmission among central neurons, as each of these systems depend in part on cholinergic signaling through nicotinic acetylcholine receptors (nAChRs). Here we showed that DNE blunts the response of the genioglossus muscle to nasal airway occlusion in lightly anesthetized rat pups. The genioglossus muscle helps keep the upper airway open and is innervated by hypoglossal motoneurons (XIIMNs). Experiments using the phrenic nerve-diaphragm preparation showed that DNE does not alter transmission across the neuromuscular junction. Accordingly, we used whole cell recordings from XIIMNs in brainstem slices to examine the influence of DNE on glutamatergic synaptic transmission under baseline conditions and in response to an acute nicotine challenge. DNE did not alter excitatory transmission under baseline conditions. Analysis of cumulative probability distributions revealed that acute nicotine challenge of P1-P2 preparations resulted in an increase in the frequency of nicotine-induced glutamatergic inputs to XIIMNs in both control and DNE. By contrast, P3-P5 DNE pups showed a decrease, rather than an increase in frequency. We suggest that this, together with previous studies showing that DNE is associated with a compensatory increase in inhibitory synaptic input to XIIMNs, leads to an excitatory-inhibitory imbalance. This imbalance may contribute to the blunting of airway protective reflexes observed in nicotine exposed animals and human infants.
Significance statement The number one risk factor for sudden infant death (SIDS) is maternal smoking. While the use of nicotine delivery devices such as e-cigarettes is increasing among women of childbearing age, reflecting the belief that the use of nicotine alone is safer than tobacco, SIDS deaths are not decreasing, suggesting that nicotine is the link between maternal smoking and SIDS. Here we show that perinatal nicotine exposure alters a major motor pathway responsible for upper airway patency during sleep. We also introduce an animal model that is well suited to probing the mechanisms underlying the link between maternal nicotine consumption and SIDS, and a phenotype that nicely models key aspects of the events believed to give rise to SIDS.
Footnotes
A. Authors report no conflict of interest
Eunice Kennedy Shriver National Institute of Child Health and Human Development; NICHD 5R01HD071302-07.
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