Remodelling at the calyx of Held–MNTB synapse in mice developing with unilateral conductive hearing loss

Abstract

Key pointsr Severe forms of hearing loss during development are well known to profoundly alter synaptic structure and function through the auditory neuraxis; however, the pre-and postsynaptic modifications that occur during development following moderate forms of unilateral hearing loss remain unknown.r We performed anatomical and electrophysiological experiments at the calyx of Held synapse in slices taken from mature mice developing with a unilateral conductive hearing loss and compared populations of synapses in the same animal that were either sound deprived or sound experienced.r Compared to normal hearing mice, we found that calyx of Held synapses that were both sound deprived and sound experienced as a result of a unilateral conductive hearing loss were (1) structurally more complex, (2) had smaller synaptic currents and a readily releasable pool size, and (3) were more excitable.r Despite these changes in structure and function, spiking fidelity within the populations maintained a continuum as in normal hearing mice such that heterogeneities remained bilaterally symmetric.r Preservations in the heterogeneity in spiking fidelity via synaptic remodelling may ensure that a functional stability important for the ability to code sound localization cues is maintained despite asymmetries in hearing experience during development.Abstract Structure and function of central synapses are profoundly influenced by experience during developmental sensitive periods. Sensory synapses, which are the indispensable interface for the developing brain to interact with its environment, are particularly plastic. In the auditory system, moderate forms of unilateral hearing loss during development are prevalent but the pre-and postsynaptic modifications that occur when hearing symmetry is perturbed are not well understood. We investigated this issue by performing experiments at the large calyx of Held synapse. Principal neurons of the medial nucleus of the trapezoid body (MNTB) are innervated by calyx of Held terminals that originate from the axons of globular bushy cells located in the contralateral ventral cochlear nucleus. We compared populations of synapses in the same animal that were either sound deprived (SD) or sound experienced (SE) after unilateral conductive hearing loss (CHL). Middle ear ossicles were removed 1 week prior to hearing onset (approx. postnatal day (P) 12) and morphological and electrophysiological approaches were applied to auditory brainstem slices taken from these mice at P17-19. Calyces in the SD and SE MNTB acquired their mature digitated morphology but these were structurally more complex than those in normal hearing mice. This was accompanied by bilateral decreases in initial EPSC amplitude and synaptic conductance despite the CHL being unilateral. During high-frequency stimulation, some SD synapses displayed short-term depression whereas others displayed short-term facilitation followed by slow depression similar to the heterogeneities observed in normal hearing mice. However SE synapses predomina...

In vivo synaptic transmission and morphology in mouse models of Tuberous sclerosis, Fragile X syndrome, Neurofibromatosis type 1, and Costello syndrome

“…The calyx of Held morphology of the WT controls in the present study matched our previous study of the Cacna1a mutant ( Di Guilmi et al, 2014 ). Type I calyces were found in none of the young-adult mice in the present and previous studies, which differs from the reported calyx morphology in two previous studies ( Grande and Wang, 2011 ; Grande et al, 2014 ). Possibly, a developmental difference is responsible for this, since these previous studies focused on P16–P19 mice, whereas in the present study and our two earlier studies, young-adult mice were used.…”

Underpinning heterogeneity in synaptic transmission by presynaptic ensembles of distinct morphological modules

“…In vivo, mature calyces are heterogeneous in morphology and spiking fidelity recapitulating the diversity observed in slices at room temperature 22,68 . Previously, we tested how physiological temperature (35 ° C) impact spiking fidelity and found that the heterogeneity reflected in spiking onset and frequency is fundamentally similar between the two conditions but emerges at higher frequencies at physiological temperature 4,21 . Nonetheless, the observed temperature-dependence of SV release and supply encompasses different mechanism, e.g.…”

“…The swellings are connected to stalks through narrow and short neck, and contain SV assemblies and multiple active zones (AZ; 4,19,20 ). We defined calyx complexity by the number of swellings, which vary across the population even after the sensitive period of auditory development 4,21 . Heterogeneity in the number of swellings on stalks has been confirmed in vivo 22 .…”

Molecular Machines Regulating the Release Probability of Synaptic Vesicles at the Active Zone

“…Finally, size and replenishment of the RRP are dynamically regulated by the level of synaptic activity. In the auditory brainstem, unilateral hearing loss results in a reduction in RRP size at the calyx of Held (Grande et al, 2014 ), while constant noise exposure induced a reversible increase in RRP size at the endbulb of Held (Ngodup et al, 2015 ). Of note, an earlier study on Ca v 1.3-KO mice, which are deaf due to non-functional glutamate release from inner hair cells, did not reveal changes in RRP size (Erazo-Fischer et al, 2007 ).…”