Abstract
Spherical bushy cells (SBCs) in the anteroventral cochlear nucleus respond to acoustic stimulation with discharges that precisely encode the phase of low-frequency sound. The accuracy of spiking is crucial for sound localization and speech perception. Compared to the auditory nerve input, temporal precision of SBC spiking is improved through the engagement of acoustically evoked inhibition. Recently, the inhibition was shown to be less precise than previously understood. It shifts from predominantly glycinergic to synergistic GABA/glycine transmission in an activity-dependent manner. Concurrently, the inhibition attains a tonic character through temporal summation. The present study provides a comprehensive understanding of the mechanisms underlying this slow inhibitory input. We performed whole-cell voltage clamp recordings on SBCs from juvenile Mongolian gerbils and recorded evoked inhibitory postsynaptic currents (IPSCs) at physiological rates. The data reveal activity-dependent IPSC kinetics, i.e., the decay is slowed with increased input rates or recruitment. Lowering the release probability yielded faster decay kinetics of the single- and short train-IPSCs at 100 Hz, suggesting that transmitter quantity plays an important role in controlling the decay. Slow transmitter clearance from the synaptic cleft caused prolonged receptor binding and, in the case of glycine, spillover to nearby synapses. The GABAergic component prolonged the decay by contributing to the asynchronous vesicle release depending on the input rate. Hence, the different factors controlling the amount of transmitters in the synapse jointly slow the inhibition during physiologically relevant activity. Taken together, the slow time course is predominantly determined by the receptor kinetics and transmitter clearance during short stimuli, whereas long duration or high frequency stimulation additionally engage asynchronous release to prolong IPSCs.
Highlights
Synaptic inhibition is mainly mediated by glycine and GABAA receptors (GlyR and GABAAR, respectively) which tightly regulate neuronal and network activities
inhibitory postsynaptic currents (IPSCs) DECAY RATE IS ACTIVITY-DEPENDENT SBCs exhibit slow inhibitory synaptic decays (Figure 1A) mediated by GlyR and GABAAR. Both the glycinergic and the GABAergic components were observed in all pharmacology experiments acquiring IPSCs with suprathreshold stimulation to evoke reliable responses
The mixed glycine-GABA transmission observed in SBCs is for the most part dominated by glycine but it still exhibits slow synaptic decays resulting in a long lasting, tonic-like inhibition
Summary
Synaptic inhibition is mainly mediated by glycine and GABAA receptors (GlyR and GABAAR, respectively) which tightly regulate neuronal and network activities. There are presynaptic terminals in the sensory systems (Wentzel et al, 1993; Protti et al, 1997; Apostolides and Trussell, 2014), cerebellum (Dumoulin et al, 2001; Rousseau et al, 2012; Husson et al, 2014) and in the spinal cord (Jonas et al, 1998; O’Brien and Berger, 1999; Keller et al, 2001; Seddik et al, 2007) that release both transmitters beyond the early postnatal development This allows for an additional variability, through activity-dependent use of transmitters (Nerlich et al, 2014), differential distribution of respective receptors at the same cell (Chéry and de Koninck, 1999), at different cells (Dugué et al, 2005; Kuo et al, 2009), or shaping the IPSC decay through action of both glycine and GABA on GlyR (Lu et al, 2008). SBCs receive acoustically evoked excitatory input from auditory nerve fibers through large calyceal terminals, the endbulds of Held (Ryugo and Sento, 1991; Isaacson and Walmsley, 1996; Nicol and Walmsley, 2002), and non-primary inhibition from neurons within the cochlear nucleus
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