Tonotopic differentiation of presynaptic neurotransmitter‐releasing machinery in the auditory brainstem during the prehearing period and its selective deficits in Fmr1 knockout mice

Abstract

Tonotopic organization is a fundamental feature of the auditory system. In the developing auditory brainstem, the ontogeny and maturation of neurotransmission progress from high to low frequencies along the tonotopic axis. To explore the underlying mechanism of this tonotopic development, we aim to determine whether the presynaptic machinery responsible for neurotransmitter release is tonotopically differentiated during development. In the current study, we examined vesicular neurotransmitter transporters and calcium sensors, two central players responsible for loading neurotransmitter into synaptic vesicles and for triggering neurotransmitter release in a calcium-dependent manner, respectively. Using immunocytochemistry, we characterized the distribution patterns of vesicular glutamate transporters (VGLUTs) 1 and 2, vesicular gamma-aminobutyric acid transporter (VGAT), and calcium sensor synaptotagmin (Syt) 1 and 2 in the developing mouse medial nucleus of the trapezoid body (MNTB). We identified tonotopic gradients of VGLUT1, VGAT, Syt1, and Syt2 in the first postnatal week, with higher protein densities in the more medial (highfrequency) portion of the MNTB. These gradients gradually flattened before the onset of hearing. In contrast, VGLUT2 was distributed relatively uniformly along the tonotopic axis during this prehearing period. In mice lacking Fragile X mental retardation protein, an mRNA-binding protein that regulates synaptic development and plasticity, progress to achieve the mature-like organization was altered for VGLUT1, Syt1, and Syt2, but not for VGAT. Together, our results identified novel organization patterns of selective presynaptic proteins in immature auditory synapses, providing a potential mechanism that may contribute to tonotopic differentiation of neurotransmission during normal and abnormal development.

Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation

“…It has been outlined that the molecular cause of FXTAS is the presence of a PM ranged (55–200 units) expansion of the CGG short-tandem-repeat (STR) locus located within the 5′-UTR of the FMR1 gene [ 7 ]. In recent years, several other neurodegenerative disorders have been associated with a PM ranged CGG STR expansion as their genetic cause [ 193 , 194 , 195 , 196 , 197 ]. These diseases include neuronal intranuclear inclusion disease (NIID), oculopharyngodistal myopathy (OPDM), and oculopharyngeal myopathy with leukoencephalopathy (OPML).…”

Volume electron microscopy reveals age-related circuit remodeling in the auditory brainstem

“…Thus, PNs of the MNTB receive glycinergic and/or GABAergic inhibitory inputs from the ipsilateral ventral nucleus of the trapezoid body (VNTB) and the MNTB itself (Kuwabara et al, 1991 ; Albrecht et al, 2014 ; Dondzillo et al, 2016 ) and excitatory cholinergic input from the superior olivary nuclei (Zhang et al, 2021 ). Since a higher expression level of GAD-67 (McCullagh et al, 2017 ), GABA vesicular transporter (VGAT; Yu and Wang, 2022 ), and glycine transporter 2 (GlyT2; McCullagh et al, 2017 ) is observed in the lateral side of the MNTB, one can propose that the increased number of non-calyceal inputs in the medial region could arise from the cholinergic innervation. However, based on the lack of sufficient knowledge, an increase of other neuromodulatory inputs cannot be precluded.…”

“…This temporary developmental gradient along the tonotopic axis is established during the critical period before the hearing onset (P12–P14). Considering that calyceal competition occurs during the same developmental windows (Rodríguez-Contreras et al, 2008 ; Sierksma et al, 2020 ) and that the maturation of neurotransmission progresses from high to low frequencies along the tonotopic axis (Yu and Wang, 2022 ), one can speculate that the only plastic window for eliminating terminals is during the critical period. Since low frequencies mature later, one can consider that not all MNTB cells located in this region mature before the end of the critical period, leaving an incomplete elimination of its calyceal inputs.…”