A time to listen: perinatal smoking affects the development of temporal sound processing

It has been known for more than 30 years that the α7 nicotinic acetylcholine receptor (nAChR) is widely expressed in the mammalian brain and is very heavily expressed in the auditory brainstem, where it is developmentally regulated. Peak expression usually occurs at about postnatal day 10 (P10) in rodents, coincident with the maturation of glutamatergic excitatory synapses. The importance of the developmental regulation and the association with excitatory synapses, however, has remained elusive. An emerging body of literature supports the view that α7 nAChRs modulate glutamatergic synapses in the adult and are involved in their maturation during the early postnatal period (Lozada et al. 2012; Koukouli & Maskos, 2015). Data from human clinical studies suggest that the perinatal exposure to smoking results in aberrant auditory processing, indicating a potential role of α7 nAChRs in this process.

In a paper in this issue of The Journal of Physiology, Baumann & Koch (2017) provide an important insight. The authors investigated how perinatal nicotine exposure affects synaptic transmission in tissue sections of the mouse ventral nucleus of the lateral lemniscus (VNLL). During development, VNLL neurons form strong and reliable synapses with excitatory inputs from octopus cells of the posteroventral cochlear nucleus. The strength of this synapse enables the VNLL to provide well‐timed inhibition to targets in the auditory midbrain. This auditory circuit has been implicated in the temporal processing of complex sounds such as speech. In several elegant experiments, the authors found that perinatal nicotine exposure acted on α7 nAChRs to greatly diminish excitatory neurotransmission in the VNLL.

Of particular interest was how the reduced excitatory transmission caused by nicotine exposure leads to degraded temporal precision of spiking in the VNLL. The authors found that spike trains evoked by electrical stimulation exhibited more failures and higher jitter in nicotine‐treated animals compared to controls. This finding is noteworthy in light of the importance of temporal information in speech processing. In addition, by observing relatively little or no change in the frequency of spontaneous EPSCs between groups, the authors determined that decreases in excitatory transmission after nicotine exposure were mediated postsynaptically. Thus changes in synaptic strength occur at the level of the VNLL. Another important finding was the developmental profile of synaptic changes associated with nicotine exposure. At P8, shortly before hearing onset, the amplitudes of evoked excitatory currents did not differ between groups. However, by P14 (after the onset of hearing) considerably weaker currents were observed in nicotine‐treated mice. Likewise, at P8, puff applications of acetylcholine induced inward currents of similar amplitude in control and nicotine‐treated animals. However, by P14, the inward current and the number of responsive neurons was reduced in controls but persisted in nicotine‐treated animals, indicating a delay in developmental downregulation of α7 nAChRs. These results suggest that the timing of the maturation of glutamatergic synapses is greatly affected by perinatal nicotine treatment, perhaps due to prolonged sensitivity to cholinergic receptor activation.

Bauman and Koch suggest that the physiological differences observed in nicotine‐treated mice, compared to controls, could be due to permanently desensitized and upregulated receptors. This interpretation is consistent with findings showing that nicotine up‐regulates α7 nAChRs. Smoking also affects methylation during development (Xu et al. 2017). The CHRNA7 proximal promoter in both human and mouse contains the necessary CgP islands allowing for the addition of a methyl group. There is evidence that promoter methylation/demethylation can control the transcription of CHRNA7, the gene that encodes the α7 nAChR (Canastar et al. 2012). Thus smoking may be an important epigenetic factor that alters the development of the excitatory synapses in the VNLL by altering the timing of α7 nAChR expression.

Deficiency in CHRNA7 is implicated in a phenotype that includes aberrant auditory processing and language delay in humans, such as autism spectrum disorders and the 15q13.2q13.3 microdeletion syndrome (Hoppman‐Chaney et al. 2013). The findings of Bauman and Koch have implications for the language delay associated with those developmental disorders. CHRNA7 deficiency does not always manifest in a phenotype. Thus, other epigenetic factors, such as smoking may be one explanation for variability in the phenotype among individuals affected by CHRNA7 deficiency or deletion.

In conclusion, the findings of Baumann and Koch suggest that disruption of excitatory synapse formation in the developing auditory brainstem may have a role in speech and language problems associated with α7 nAChR dysfunction. The recognition and interpretation of speech relies on temporally precise auditory processing. Thus, alterations in α7 nAChR signalling that degrade the strength and timing of auditory responses could have profound consequences. In addition, the delay in developmental downregulation of α7 nAChRs after chronic nicotine exposure may contribute to language delay.

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Competing interests

None declared.