Abstract
In developing sensory systems, elaborate morphological connectivity between peripheral cells and first-order central neurons emerges via genetic programming before the onset of sensory activities. However, how the first-order central neurons acquire the capacity to interface with peripheral cells remains elusive. By making patch-clamp recordings from mouse brainstem slices, we found that a subset of neurons in the cochlear nuclei, the first central station to receive peripheral acoustic impulses, exhibits spontaneous firings (SFs) as early as at birth, and the fraction of such neurons increases during the prehearing period. SFs are reduced but not eliminated by a cocktail of blockers for excitatory and inhibitory synaptic inputs, implicating the involvement of intrinsic pacemaker channels. Furthermore, we demonstrate that these intrinsic firings (IFs) are largely driven by hyperpolarization- and cyclic nucleotide-gated channel (HCN) mediated currents (Ih), as evidenced by their attenuation in the presence of HCN blockers or in neurons from HCN1 knockout mice. Interestingly, genetic deletion of HCN1 cannot be fully compensated by other pacemaker conductances and precludes age-dependent up regulation in the fraction of spontaneous active neurons and their firing rate. Surprisingly, neurons with SFs show accelerated development in excitability, spike waveform and firing pattern as well as synaptic pruning towards mature phenotypes compared to those without SFs. Our results imply that SFs of the first-order central neurons may reciprocally promote their wiring and firing with peripheral inputs, potentially enabling the correlated activity and crosstalk between the developing brain and external environment.
Highlights
Spontaneous neuronal activity is a characteristic feature in the majority of developing sensory systems, such as the spinal cord, cerebellum, auditory and visual systems (Mohajerani and Cherubini, 2005; Kirkby et al, 2013; Del Rio-Bermudez et al, 2016)
We found that a fraction of cochlear nucleus (CN) neurons already exhibited spontaneous firings (SFs) as early as P0–1 (Figure 1C; neurons with or without SFs are designated as SF(+) and SF(−), being 27.8% (n = 15) and 72.2% (n = 39), respectively, despite the fact that the presumed origin of upstream spontaneous activity had been cut during slice preparation)
This study demonstrates that a subset of the first central neurons in the auditory brainstem is capable of firing spontaneously, independent of synaptic inputs, and that this spontaneous activity during the early postnatal period is intrinsically driven by hyperpolarization- and cyclic nucleotide-gated channel (HCN) channel-mediated Ih
Summary
Spontaneous neuronal activity is a characteristic feature in the majority of developing sensory systems, such as the spinal cord, cerebellum, auditory and visual systems (Mohajerani and Cherubini, 2005; Kirkby et al, 2013; Del Rio-Bermudez et al, 2016). Tritsch et al (2007) discovered that supporting cells within Kölliker’s organ spontaneously release ATP to depolarize nearby IHCs and evoke glutamate release, driving bursts of firing activity in spiral ganglion neurons (SGNs) and propagation of spikes via auditory nerves into downstream nuclei (Tritsch et al, 2007). These compelling studies led to the prevailing view that spontaneous activity in the periphery plays an instructive role in the development of the central auditory brainstem prior to external sensory-evoked activity. It remains unknown whether the first-order central auditory neurons are capable of spontaneous discharge without peripheral inputs during the early postnatal stage; and if so, what the origin and molecular substrates underlying such activity are
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