Activity-Dependent Transmission and Integration Control the Timescales of Auditory Processing at an Inhibitory Synapse

Abstract

To capture the context of sensory information, neural networks must process input signals across multiple timescales. In the auditory system, a prominent change in temporal processing takes place at an inhibitory GABAergic synapse in the dorsal nucleus of the lateral lemniscus (DNLL). At this synapse, inhibition outlasts the stimulus by tens of milliseconds, such that it suppresses responses to lagging sounds, and is therefore implicated in echo suppression. Here, we untangle the cellular basis of this inhibition. We demonstrate with in vivo whole-cell patch-clamp recordings in Mongolian gerbils that the duration of inhibition increases with sound intensity. Activity-dependent spillover and asynchronous release translate the high presynaptic firing rates found in vivo into a prolonged synaptic output in acute slice recordings. A key mechanism controlling the inhibitory time course is the passive integration of the hyperpolarizing inhibitory conductance. This prolongation depends on the synaptic conductance amplitude. Computational modeling shows that this prolongation is a general mechanism and relies on a non-linear effect caused by synaptic conductance saturation when approaching the GABA reversal potential. The resulting hyperpolarization generates an efficient activity-dependent suppression of action potentials without affecting the threshold or gain of the input-output function. Taken together, the GABAergic inhibition in the DNLL is adjusted to the physiologically relevant duration by passive integration of inhibition with activity-dependent synaptic kinetics. This change in processing timescale combined with the reciprocal connectivity between the DNLLs implements a mechanism to suppress the distracting localization cues of echoes and helps to localize the initial sound source reliably.

Electrogenic N‐methyl‐D‐aspartate receptor signaling enhances binaural responses in the adult brainstem

“…Series resistance in whole‐cell voltage‐clamp was compensated to a residual 3 MOhm. The liquid junction potentials were calculated on the basis of ion concentrations and corrected for (Ammer et al ., ). For current‐clamp recordings, the internal solution consisted of (in m m ): 145 K‐gluconate, 4.5 KCl, 15 HEPES, 2 Mg‐ATP, 2 K‐ATP, 0.3 Na 2 ‐GTP, 7.5 Na 2 ‐Phospocreatine, 5 K‐EGTA (pH 7.3, liquid junction potential 17 mV).…”

Minimal Number of Required Inputs for Temporally Precise Action Potential Generation in Auditory Brainstem Nuclei

“…Taken together, DNLL neurons rest close to the action potential threshold, and small AMPAR currents that ride on a slowly integrated depolarizing NMDAR current trigger action potential generation at input frequency up to 100 Hz. Possibly this high excitability is required to overcome hyperpolarizing inhibition during sound stimulations (Yang and Pollak, 1994;Ammer et al, 2015;Siveke et al, 2019) or, if present in a tonic way, due to some spontaneously active contralateral DNLL neurons (Bajo et al, 1998). Despite this high excitability and the fact, that some of the DNLL neurons can fire high frequencies in vivo (Kuwada et al, 2006;Siveke et al, 2006) and in response to in vitro current injections (Ahuja and Wu, 2000;Ammer et al, 2012), their maximal output frequency appears limited by the severe synaptic depression and postsynaptic adaptive mechanisms.…”

Optogenetic Control of Neural Circuits in the Mongolian Gerbil

“…Moreover, it represents a good example for a nucleus in which direct electrical stimulation of neurons is impossible, because large numbers of fibers projecting to the MSO and LSO pass through it and would be electrically activated as well. The DNLL has been hypothesized to be crucial in the context of echo suppression and the precedence effect ( Cremer, 1948 ; Wallach et al, 1949 ; Haas, 1951 ; Shneiderman et al, 1988 ; Ito et al, 1996 ; Kelly et al, 1996 ; Pecka et al, 2007 ; Ammer et al, 2015 ). The IC is a central structure in sound processing ( Pollak et al, 2003 ).…”