Morphological and Functional Continuum Underlying Heterogeneity in the Spiking Fidelity at the Calyx of Held SynapseIn Vitro

Abstract

Reliable neuronal spiking is critical for a myriad of computations performed by neural circuits. This is particularly evident for sound localization cues in the auditory brainstem circuits that detect timing and intensity differences of sounds arriving at two ears. The calyx of Held-principal neuron synapse in the medial nucleus of the trapezoid body (MNTB) in this circuit is traditionally viewed as a reliable relay, which converts contralateral excitatory inputs to inhibitory outputs to ipsilateral superior olive neurons that code interaural timing and intensity differences. However, recent studies demonstrated large variability in the incidence of postsynaptic spike failures at this synapse, challenging the view that this synapse is a fail-safe relay. Using combined imaging and paired recordings in mature (P16 -P19) mouse brainstem slices, we show that spike failure rates of MNTB neurons are strongly correlated with differences in gross morphology of the calyx terminal and quantal properties under standard in vitro-and in vivo-like conditions. MNTB neurons innervated by calyces with simple morphologies (mainly digits) express strong short-term synaptic depression and a high incidence of spike failures after high-frequency stimulation. Conversely, MNTB neurons innervated by structurally complex calyces (digits and numerous bouton-like swellings) exhibit initial facilitation followed by slow depression and very few spike failures. Our results indicate that the calyx of Held-MNTB synapse is likely organized as a structural and functional continuum, in that correlated heterogeneities in calyx morphology and short-term plasticity serve as a filter for regulating the inhibition delivered to superior olive neurons during sound localization.

Superpriming of synaptic vesicles as a common basis for intersynapse variability and modulation of synaptic strength

“…Some morphological variability seen among calyces of older mice (P16-19) has been reported to correlate with functional parameters (31). Here we explore possible mechanisms that generate functional heterogeneity among calyces.…”

“…AP-evoked excitatory postsynaptic currents (EPSCs) vary in amplitude by more than a factor of 5 among calyx synapses and display divergent STP patterns (31). We show that such variability is similar to differences that can be experimentally induced by application of the DAG analog phorbol 12,13-dibutyrate (PdBu) and we explore the hypothesis that intrinsic heterogeneity of synaptic strength among synapses is caused by different degrees of activation of the PLC-DAG pathway, possibly due to the action of slow modulatory transmitter systems.…”

Glycinergic inhibition to the medial nucleus of the trapezoid body shows prominent facilitation and can sustain high levels of ongoing activity

“…This view is inconsistent with the observation that transmission at the calyx is not entirely fail-safe, and in some cases incoming action potentials do not result in spiking of MNTB principal neurons-at least in some species and under some circumstances (Grande and Wang 2011;Hermann et al 2007Hermann et al , 2009Klug 2011;Kopp-Scheinpflug et al 2003Lorteije et al 2009). Moreover, MNTB neurons themselves receive synaptic inhibition (Albrecht et al 2014;Awatramani et al 2004;Green and Sanes 2005;Smith et al 1998;Thompson and Schofield 2000), which modifies firing patterns of MNTB neurons (Green and Sanes 2005; KoppScheinpflug et al 2008;Tolnai et al 2008).…”

“…Besides temporal precision, it has been argued that one reason for the large excitatory signals is that the calyx of Held/MNTB system is a fail-safe relay station that simply converts glutamatergic excitation into glycinergic inhibition without any significant spike train transformation (Borst and Soria van Hoeve 2012;Crins et al 2011;McLaughlin et al 2008;Smith et al 1998;Taschenberger and von Gersdorff 2000). The sign inversion is needed because neural inhibition is required in the sound localization process in which the MNTB participates (Brand et al 2002;Caird and Klinke 1983).This view is inconsistent with the observation that transmission at the calyx is not entirely fail-safe, and in some cases incoming action potentials do not result in spiking of MNTB principal neurons-at least in some species and under some circumstances (Grande and Wang 2011;Hermann et al 2007Hermann et al , 2009Klug 2011;Kopp-Scheinpflug et al 2003Lorteije et al 2009). Moreover, MNTB neurons themselves receive synaptic inhibition (Albrecht et al 2014;Awatramani et al 2004;Green and Sanes 2005;Smith et al 1998;Thompson and Schofield 2000), which modifies firing patterns of MNTB neurons (Green and Sanes 2005; KoppScheinpflug et al 2008;Tolnai et al 2008).…”

Molecularly and structurally distinct synapses mediate reliable encoding and processing of auditory information

“…These most complex calyces exhibited initial facilitation followed by slow depression and only very few spike failures. This can be explained by the higher number of available vesicles and release sites (Grande and Wang, 2011). Moreover, the contact area to the principal cell is enlarged in more complex terminals likely influencing the activation strength and speed of the postsynaptic cell.…”