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

KEY POINTS: Chronic perinatal nicotine exposure causes abnormal auditory brainstem responses and auditory processing deficits in children and animal models. 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. Perinatal nicotine exposure caused a massive reduction in the amplitude of the excitatory input current. This caused a profound decrease in the number and temporal precision of spikes in these neurons. 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.

Heterogeneity of Intrinsic and Synaptic Properties of Neurons in the Ventral and Dorsal Parts of the Ventral Nucleus of the Lateral Lemniscus.

The ventral nucleus of the lateral lemniscus (VNLL) provides a major inhibitory projection to the inferior colliculus (IC). Neurons in the VNLL respond with various firing patterns and different temporal precision to acoustic stimulation. The present study investigates the underlying intrinsic and synaptic properties of various cell types in different regions of the VNLL, using in vitro electrophysiological recordings from acute brain slices of mice and immunohistochemistry. We show that the biophysical membrane properties and excitatory input characteristics differed between dorsal and ventral VNLL neurons. Neurons in the ventral VNLL displayed an onset-type firing pattern and little hyperpolarization-activated current (Ih). Stimulation of lemniscal inputs evoked a large all-or-none excitatory response similar to Calyx of Held synapses in neurons in the lateral part of the ventral VNLL. Neurons that were located within the fiber tract of the lateral lemniscus, received several and weak excitatory input fibers. In the dorsal VNLL onset-type and sustained firing neurons were intermingled. These neurons showed large Ih and were strongly immunopositive for the hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) subunit. Both neuron types received several excitatory inputs that were weaker and slower compared to ventrolateral VNLL neurons. Using a mouse model that expresses channelrhodopsin under the promotor of the vesicular GABA transporter (VGAT) suggests that dorsal and ventral neurons were inhibitory since they were all depolarized by light stimulation. The diverse membrane and input properties in dorsal and ventral VNLL neurons suggest differential roles of these neurons for sound processing.

Tonotopic organization of the hyperpolarization-activated current (Ih) in the mammalian medial superior olive.

Neuronal membrane properties can largely vary even within distinct morphological cell classes. The mechanisms and functional consequences of this diversity, however, are little explored. In the medial superior olive (MSO), a brainstem nucleus that performs binaural coincidence detection, membrane properties at rest are largely governed by the hyperpolarization-activated inward current (Ih) which enables the temporally precise integration of excitatory and inhibitory inputs. Here, we report that Ih density varies along the putative tonotopic axis of the MSO with Ih being largest in ventral, high-frequency (HF) processing neurons. Also Ih half-maximal activation voltage and time constant are differentially distributed such that Ih of the putative HF processing neurons activate faster and at more depolarized levels. Intracellular application of saturating concentrations of cyclic AMP removed the regional difference in hyperpolarization-activated cyclic nucleotide gated (HCN) channel activation, but not Ih density. Experimental data in conjunction with a computational model suggest that increased Ih levels are helpful in counteracting temporal summation of phase-locked inhibitory inputs which is particularly prominent in HF neurons.