Perinatal nicotine exposure impairs the maturation of glutamatergic inputs in the auditory brainstem

Abstract

Key pointsr Chronic perinatal nicotine exposure causes abnormal auditory brainstem responses and auditory processing deficits in children and animal models.r The effect of perinatal nicotine exposure on synaptic maturation in the auditory brainstem was investigated in granule cells in the ventral nucleus of the lateral lemniscus, which receive a single calyx-like input from the cochlear nucleus.r Perinatal nicotine exposure caused a massive reduction in the amplitude of the excitatory input current.r This caused a profound decrease in the number and temporal precision of spikes in these neurons.r Perinatal nicotine exposure delayed the developmental downregulation of functional nicotinic acetylcholine receptors on these neurons.Abstract Maternal smoking causes chronic nicotine exposure during early development and results in auditory processing deficits including delayed speech development and learning difficulties. Using a mouse model of chronic, perinatal nicotine exposure we explored to what extent synaptic inputs to granule cells in the ventral nucleus of the lateral lemniscus are affected by developmental nicotine treatment. These neurons receive one large calyx-like input from octopus cells in the cochlear nucleus and play a role in sound pattern analysis, including speech sounds. In addition, they exhibit high levels of α7 nicotinic acetylcholine receptors, especially during early development. Our whole-cell patch-clamp experiments show that perinatal nicotine exposure causes a profound reduction in synaptic input amplitude. In contrast, the number of inputs innervating each neuron and synaptic release properties of this calyx-like synapse remained unaltered. Spike number and spiking precision in response to synaptic stimulation were greatly diminished, especially for later stimuli during a stimulus train. Moreover, chronic nicotine exposure delayed the developmental downregulation of functional nicotinic acetylcholine receptors on these neurons, indicating a direct action of nicotine in this brain area. This presumably direct effect of perinatal nicotine exposure on synaptic maturation in the auditory brainstem might be one of the underlying causes for auditory processing difficulties in children of heavy smoking mothers.

Minimal Number of Required Inputs for Temporally Precise Action Potential Generation in Auditory Brainstem Nuclei

“…The biophysical activity pattern of P9/10 and mature neurons in the ventral nucleus of the lateral lemniscus (VNLL), medial nucleus of the trapezoid body (MNTB), medial superior olive (MSO) and dorsal nucleus of the lateral lemniscus (DNLL) are established from long step current injections (Banks and Smith, 1992;Forsythe, 1994;Ahuja and Wu, 2000;Scott et al, 2005;Chirila et al, 2007;Porres et al, 2011;Ammer et al, 2012;Franzen et al, 2015;Baumann and Koch, 2017). Our comparative data corroborated the described onset action potentials in MNTB, MSO, and VNLL neurons and the continuous firing from DNLL neurons (Figure 1).…”

“…Often observed is a developmental drop in input resistance (Magnusson et al, 2005;Scott et al, 2005;Chirila et al, 2007;Hoffpauir et al, 2010;Rusu and Borst, 2011;Franzen et al, 2015Franzen et al, , 2020 based on the upregulation of ion channels (Scott et al, 2005;Hassfurth et al, 2009;Khurana et al, 2012;Franzen et al, 2015). In this developmental period synaptic current accelerates by changes in AMPA receptors (Bellingham et al, 1998;Taschenberger and von Gersdorff, 2000;Joshi and Wang, 2002;Koike-Tani et al, 2005;Youssoufian et al, 2005;Ammer et al, 2012;Felix and Magnusson, 2016;Baumann and Koch, 2017;Franzen et al, 2020) and a reduction or loss of synaptic NMDA receptors (Bellingham et al, 1998;Steinert et al, 2010;Case et al, 2011;Hirtz et al, 2011;Ammer et al, 2012;Winters and Golding, 2018;Franzen et al, 2020). The neuronal morphology remodels by changes in the dendritic arbor (Sanes et al, 1992;Rietzel and Friauf, 1998;Rautenberg et al, 2009) and somatic size (Franzen et al, 2015).…”

Nicotinic acetylcholine receptor subunit α7-knockout mice exhibit degraded auditory temporal processing

“…Thus cholinergic input likely aids in establishing robust connections. Consistent with this notion, a recent study demonstrated that disruption of ␣ 7 -nAChR signaling during VNLL development leads to delays of the maturation of temporal processing (Baumann and Koch 2017). We found that ␣ 7 -receptor KO mice contained SPON and VNLL neurons that exhibited degraded temporal processing.…”

“…Cholinergic signaling, particularly during development, is important for establishing precise temporal properties of auditory neurons (Baumann and Koch 2017). In other neural systems apart from audition, the ␣ 7 -nAChR is critical for establishing glutamatergic synapses during development (Halff Fig.…”

“…Dysregulation of the ␣ 7 -nAChR degrades the normally strong and reliable glutamatergic synapses of developing rodent auditory brainstem pathways (Baumann and Koch 2017;Morley and Felix 2017). In other systems, it has been demonstrated that ␣ 7 -nAChR is obligatory for innervation; permanent synaptic deficits occur in its absence (Lozada et al 2012).…”