Tuning auditory synapses for resilience, reliability and precision

Field: Neuroscience (Life Sciences)

The neuronal circuits that compute sound localization are found in the superior olivary complex (SOC) of the mammalian auditory brainstem. These circuits contain specialized synapses that can faithfully transmit prolonged incoming sound signals with great temporal precision. This sustained, precise and reliable processing of sound signals allows the SOC circuits to use both the timing and intensity of sound in the two ears as binaural cues for computing the locus of sound sources. The nucleus of the lateral superior olive (LSO) in the SOC is essential for the interaural processing of high-frequency sound signals (Tollin et al. 2008). In the LSO excitatory inputs from the spherical bushy cells of the ipsilateral cochlear nucleus (SBC–LSO) converge with the inhibitory innervations from the principal cells of the medial nucleus of the trapezoid body (MNTB; Grothe & Pecka, 2014). The LSO thus functions as the first stage in the auditory circuit whereby both excitatory (SBC–LSO) and inhibitory (MNTB–LSO) sound cues converge from opposite sides of the head (Sommer et al. 1993). The LSO juncture in the SOC circuit is thus pivotal for the precise and accurate localization of high-frequency sounds in space. Several synapses in the cochlea and auditory brainstem have evolved specialized morphological features permitting sustained and reliable high-frequency information transmission. For example, synaptic ribbons in hair cells, and endbulbs and calyceal nerve terminals in the brainstem, contain multiple active zones each with several docked vesicles that constitute a large readily releasable pool (Yu & Goodrich, 2014; Wichmann, 2015). Abundant mitochondria are also found near these active zones, presumably to fuel the high rates of transmitter release (Perkins et al. 2015). However, the MNTB–LSO inhibitory synapses possess conventional presynaptic bouton-type morphology, but nevertheless maintain high synaptic reliability and retain the ability to fire in temporally precise time windows. By contrast, the hippocampal glutamatergic CA3–CA1 synapses and the GABAergic synapses between the entorhinal cortex and dentate granule cells (EC–DG), which also express conventional synaptic bouton architecture, exhibit greatly reduced fidelity and precision in response to high-frequency challenges. What then, is the cause of this increased synaptic fidelity and temporal precision during sustained high-frequency activity in the seemingly 'conventional' bouton-type MNTB–LSO synapses? In this issue of The Journal of Physiology, Krächan et al. (2017) performed a detailed study with elegant data analysis in which they compared the functional synaptic properties of the glycinergic MNTB–LSO synapses in the auditory brainstem to both the glutamatergic CA3–CA1 and the GABAergic EC–DG synapses in the hippocampus. Upon prolonged stimulation, hippocampal synapses underwent marked short-term depression of synaptic currents when compared to the MNTB–LSO synapse. Namely, afferent fibre stimulation at 10 Hz in the hippocampal formation reduced postsynaptic currents (PSCs) to ∼40% and ∼30% of baseline in CA3–CA1 and EC–DG synapses, respectively. However, the MNTB–LSO PSCs depressed to only ∼60% of baseline during 10 Hz stimulation, and not until synaptic transmission was driven at 50 Hz was the MNTB–LSO synapse observed to depress to a similar level as in the hippocampus (∼45% of baseline). This is especially remarkable given that the MNTB–LSO synapses were obtained from immature pre-hearing mouse pups. Furthermore, the MNTB–LSO synapses exhibited higher temporal precision (or less jitter) in transmitter release when compared to both hippocampal synapse types under the same high-frequency challenges. These data suggest that MNTB–LSO synapses possess synaptic refinements that allow them to resist synaptic fatigue independently of unusual presynaptic morphological specializations. How do MNTB–LSO synapses maintain high synaptic fidelity? Krächan et al. 2017 show that efficient processes are in place to provide increased quantal content and rapid synaptic vesicle replenishment that are likely to aid in the maintenance of high-frequency transmission. During prolonged high-frequency activity, a depressed steady-state PSC is maintained by continuous multivesicular release from a large readily releasable pool that is matched by rapid synaptic vesicle pool replenishment (von Gersdorff & Borst, 2002). Additionally, depleting the pool of synaptic vesicles activates ATP- and Ca2+-dependent pool refilling mechanisms (Hosoi et al. 2007). Moreover, during afferent fibre stimulation, some MNTB–LSO synapses may initially facilitate and then show depression, whereas others may exhibit just PSC short-term depression. How this short-term plasticity is regulated by release probability, vesicle pool size and a potential 'super-priming' of docked vesicles at some active zones remains unclear at the seemingly indefatigable MNTB–LSO synapses (Taschenberger et al. 2016). Although the mechanisms regulating synaptic vesicle exocytosis are fairly well understood (Südhof, 2004), mobilization of synaptic vesicles from a hypothesized reserve pool to the readily releasable pool during ongoing activity is less well understood. It is conceivable that the MNTB–LSO synapses contain specialized and thus more efficient mechanisms for this vesicle mobilization process, perhaps via reduced viscosity in the cytoplasm (Rothman et al. 2016); however, the molecular machinery involved remains unknown. Similarly, synaptic vesicle membrane retrieval may occur via different endocytic pathways with distinct kinetics (Delvendahl et al. 2016). The specific mode by which vesicle recycling occurs may contribute to the synaptic fidelity, but the molecular players involved at the MNTB–LSO synapse remain to be fully elucidated. In conclusion, these resilient and faithful synapses of the auditory system can outperform the smart but unreliable synapses of the hippocampus.