Chloride cotransporters, chloride homeostasis, and synaptic inhibition in the developing auditory system

Friauf, Eckhard; Rust, Marco B.; Schulenborg, Thomas; Hirtz, Jan J.

doi:10.1016/j.heares.2011.05.012

Cited by 27 publications

(26 citation statements)

References 251 publications

(288 reference statements)

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“…E GABA was À91.3 ± 2.4 mV (n = 8; Figure 1D) and therefore 15 mV lower than the average membrane potential of À76.2 ± 0.8 mV (n = 55). Thus, similar to other mammalian auditory brainstem structures [23], GABAergic inhibition is hyperpolarizing in the DNLL with an estimated chloride concentration of 4.5 mM ( Figure 1D). Next, we verified that inhibition evoked through the commissure of Probst is indeed mediated exclusively through GABA A receptors [21,24].…”

Section: Resultssupporting

confidence: 79%

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

2015

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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.

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Section: Resultssupporting

confidence: 79%

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

2015

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“…KCC2 is present throughout the central nervous system, but is particularly highly expressed in the hippocampus, hypothalamus, brainstem, and motor neurons of the spinal cord (Vinay and Jean-Xavier, 2008; Blaesse et al, 2009). Developmental up-regulation of KCC2 expression strengthens hyperpolarizing inhibition (Cherubini et al, 2011; Friauf et al, 2011). Consequently, acquired loss of KCC2 function in mature neurons will lead to hyperexcitability and seizures due to less hyperpolarizing inhibitory inputs (Wake et al, 2007; Vinay and Jean-Xavier, 2008; Boulenguez et al, 2010; Arion and Lewis, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Early in development the sodium-potassium-chloride co-transporter type 1 (NKCC1) maintains a high intracellular chloride ([Cl − ] i ) concentration in most neurons and hence Cl − -mediated synaptic events are depolarizing (Cherubini et al, 2011; Friauf et al, 2011; but see Balakrishnan et al, 2003 for an exception). It is postulated that early in development, inhibitory synapses generate excitatory postsynaptic potentials (EPSPs) that act to stabilize synapse formation, and that as neurons mature there is a switch to expression of neuronal potassium chloride co-transporter type 2 (KCC2), driving a low [Cl − ] i and supporting hyperpolarizing IPSPs (Kandler and Gillespie, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…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 changes in phosphorylation (Casula et al, 2001; Blaesse et al, 2006; Chamma et al, 2012). As [Cl − ] i declines, the driving force favors influx of Cl − ions which strengthens IPSPs and synaptic inhibition (Lohrke et al, 2005; Friauf et al, 2011; Ben-Ari et al, 2012). In mature neurons, KCC2 can be down-regulated under pathophysiological conditions, reducing the effectiveness of inhibition and causing hyperexcitability (Wake et al, 2007; Hewitt et al, 2009; Boulenguez et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Nitric oxide signaling modulates synaptic inhibition in the superior paraolivary nucleus (SPN) via cGMP-dependent suppression of KCC2

Yassin

Radtke‐Schuller

Asraf

et al. 2014

Front. Neural Circuits

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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).

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“…Such co-transmission allows for an additional variability, enabling target dependent use of transmitters at the same cell (Chéry and de Koninck, 1999; Nerlich et al, 2014b), at different cells (Dugué et al, 2005; Kuo et al, 2009), or fine-tuning of inhibitory strength and its time course (Russier et al, 2002; Awatramani et al, 2005; González-Forero and Alvarez, 2005; Lu et al, 2008; Coleman et al, 2011; Apostolides and Trussell, 2013; Nerlich et al, 2014b). Synaptic inhibition in mature auditory brainstem circuits, playing an important role in encoding acoustic cues used for sound source localization, can be almost exclusively attributed to the action of glycine (Grothe, 2003; Awatramani et al, 2004; Magnusson et al, 2005; Kopp-Scheinpflug et al, 2008; Pecka et al, 2008; Couchman et al, 2010; Friauf et al, 2011; Roberts et al, 2013; Myoga et al, 2014). In the mammalian cochlear nucleus, however, the activity of spherical bushy cells (SBCs) that receive large glutamatergic auditory nerve fiber terminals, is shaped by a dual glycine-GABA transmission (Nerlich et al, 2014a).…”

Section: Introductionmentioning

confidence: 99%

Developmental Shift of Inhibitory Transmitter Content at a Central Auditory Synapse

Nerlich

Rübsamen

Milenković

2017

Front. Cell. Neurosci.

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Synaptic inhibition in the CNS is mostly mediated by GABA or glycine. Generally, the use of the two transmitters is spatially segregated, but there are central synapses employing both, which allows for spatial and temporal variability of inhibitory mechanisms. Spherical bushy cells (SBCs) in the mammalian cochlear nucleus receive primary excitatory inputs through auditory nerve fibers arising from the organ of Corti and non-primary inhibition mediated by a dual glycine-GABA transmission. Slow kinetics IPSCs enable activity dependent tonic-like conductance build up, functioning as a gain control by filtering out small or temporally imprecise EPSPs. However, it remained elusive whether GABA and glycine are released as content of the same vesicle or from distinct presynaptic terminals. The developmental profile of quantal release was investigated with whole cell recordings of miniature inhibitory postsynaptic currents (mIPSCs) from P1–P25 SBCs of Mongolian gerbils. GABA is the initial transmitter eliciting slow-rising and -decaying events of relatively small amplitudes, occurring only during early postnatal life. Around and after hearing onset, the inhibitory quanta are predominantly containing glycine that—with maturity—triggers progressively larger and longer mIPSC. In addition, GABA corelease with glycine evokes mIPSCs of particularly large amplitudes consistently occurring across all ages, but with low probability. Together, these results suggest that GABA, as the primary transmitter released from immature inhibitory terminals, initially plays a developmental role. In maturity, GABA is contained in synaptic vesicles only in addition to glycine to increase the inhibitory potency, thereby fulfilling solely a modulatory function.

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Chloride cotransporters, chloride homeostasis, and synaptic inhibition in the developing auditory system

Cited by 27 publications

References 251 publications

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

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

Nitric oxide signaling modulates synaptic inhibition in the superior paraolivary nucleus (SPN) via cGMP-dependent suppression of KCC2

Developmental Shift of Inhibitory Transmitter Content at a Central Auditory Synapse

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