Abstract
Glycinergic inhibition plays a central role in the auditory brainstem circuitries involved in sound localization and in the encoding of temporal action potential firing patterns. Modulation of this inhibition has the potential to fine-tune information processing in these networks. Here we show that nitric oxide (NO) signaling in the auditory brainstem (where activity-dependent generation of NO is documented) modulates the strength of inhibition by changing the chloride equilibrium potential. Recent evidence demonstrates that large inhibitory postsynaptic currents (IPSCs) in neurons of the superior paraolivary nucleus (SPN) are enhanced by a very low intracellular chloride concentration, generated by the neuronal potassium chloride co-transporter (KCC2) expressed in the postsynaptic neurons. Our data show that modulation by NO caused a 15 mV depolarizing shift of the IPSC reversal potential, reducing the strength of inhibition in SPN neurons, without changing the threshold for action potential firing. Regulating inhibitory strength, through cGMP-dependent changes in the efficacy of KCC2 in the target neuron provides a postsynaptic mechanism for rapidly controlling the inhibitory drive, without altering the timing or pattern of the afferent spike train. Therefore, this NO-mediated suppression of KCC2 can modulate inhibition in one target nucleus (SPN), without influencing inhibitory strength of other target nuclei (MSO, LSO) even though they are each receiving collaterals from the same afferent nucleus (a projection from the medial nucleus of the trapezoid body, MNTB).
Highlights
The superior olivary complex (SOC) consists of groups of highly specialized brainstem nuclei that compute various acoustic features in sound location processing
The immunohistochemistry shows that KCC2 is expressed postsynaptically in the LSO, MSO and superior paraolivary nucleus (SPN) of both mouse and gerbil and this mirrors the presynaptic labeling for glycine transporter type 2 (GlyT2) (Figure 1 insets)
Given that individual medial nucleus of the trapezoid body (MNTB) neurons are projecting to multiple nuclei and firing patterns are the same for each target, it is important to understand how the inhibitory synaptic strength can be independently modulated in each target nucleus to fine-tune local synaptic actions
Summary
The superior olivary complex (SOC) consists of groups of highly specialized brainstem nuclei that compute various acoustic features in sound location processing. The MNTB is the major inhibitory hub within the SOC, with individual MNTB neurons providing collateral projections to multiple, functionally diverse targets (Banks and Smith, 1992; Sommer et al, 1993) where they serve fast and temporally precise inhibition, similar to the role of fast spiking inhibitory interneurons in other brain circuits (Bartos et al, 2002; Tepper et al, 2004) This common source of afferent inhibition (the MNTB) raises the question of what mechanisms are available to modulate the synaptic responses of the individual postsynaptic targets which serve differing roles in these diverse computational functions. The trafficking, cell surface expression and transport-activity of KCC2 are closely controlled by neuronal activity (Fiumelli et al, 2005; Wake et al, 2007) with increased KCC2 activity caused by protein oligomerization and Frontiers in Neural Circuits www.frontiersin.org
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