Modulation of synaptic input by GABAB receptors improves coincidence detection for computation of sound location

Key points Organisms localise low frequencies using interaural time disparities (ITDs) in which specialized neurones in the medial superior olive (MSO) compute submillisecond differences in arrival time of sounds to each ear, a value that varies systematically with sound location. These neurones compute sound location over a 1012 fold range in sound intensities, despite large intensity-dependent changes in input strength. Modulation of synaptic gain has been suggested as a mechanism to maintain accurate ITD processing. Here we show that activation of GABAB receptors suppresses both the excitatory and inhibitory inputs to the MSO and alters the kinetics of inhibitory synaptic currents. Using in vitro physiological methods and computational modelling, we show that the modulation by GABAB receptor activation contributes to spatial tuning of MSO neurones. These results contribute to the understanding of how neurones maintain computational stability under widely varying input conditions. Abstract Interaural time disparities (ITDs) are the primary cues for localisation of low-frequency sound stimuli. ITDs are computed by coincidence-detecting neurones in the medial superior olive (MSO) in mammals. Several previous studies suggest that control of synaptic gain is essential for maintaining ITD selectivity as stimulus intensity increases. Using acute brain slices from postnatal day 7 to 24 (P7P24) Mongolian gerbils, we confirm that activation of GABAB receptors reduces the amplitude of excitatory and inhibitory synaptic currents to the MSO and, moreover, show that the decay kinetics of IPSCs are slowed in mature animals. During repetitive stimuli, activation of GABAB receptors reduced the amount of depression observed, while PSC suppression and the slowed kinetics were maintained. Additionally, we used physiological and modelling approaches to test the potential impact of GABAB activation on ITD encoding in MSO neurones. Current clamp recordings from MSO neurones were made while pharmacologically isolated excitatory inputs were bilaterally stimulated using pulse trains that simulate ITDs in vitro. MSO neurones showed strong selectivity for bilateral delays. Application of both GABAB agonists and antagonists demonstrate that GABAB modulation of synaptic input can sharpen ITD selectivity. We confirmed and extended these results in a computational model that allowed for independent manipulation of each GABAB-dependent effect. Modelling suggests that modulation of both amplitude and kinetics of synaptic inputs by GABAB receptors can improve precision of ITD computation. Our studies suggest that in vivo modulation of synaptic input by GABAB receptors may act to preserve ITD selectivity across various stimulus conditions.