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

Yassin L, Radtke-Schuller S, Asraf H, Grothe B, Hershfinkel M, Forsythe ID, Kopp-Scheinpflug C - Front Neural Circuits (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Neurobiology, Department Biology II, Ludwig-Maximilians-University Munich Planegg-Martinsried, Germany.

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).

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Nitric oxide suppresses gap-detection on a cellular level. (A) Mouse SPN neurons show offset firing in responses to gaps of different durations (60–20 ms) embedded in trains of electrically evoked IPSPs. (B) Bath application of an NO donor reduced the number of action potentials per gap and delayed the action potential within the gap so that only longer gaps were detected. Stimulus artifacts were removed for clarity. (C) The number of evoked action potentials increased with gap duration in controls (black bars), but was never more than one with NO (white bars). (D) Repetitive stimulation (10 IPSP trains) was used to estimate gap-detection success, which is plotted here as % offset action potentials against gap duration. Threshold was defined as 50% success (dashed line); controls (black) reliably detected gaps of 20 ms or longer, but following NO, gap-detection thresholds increased to 60 ms or longer. Data plotted as mean ± s.e.m. (n indicated on the respective graph).
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Figure 7: Nitric oxide suppresses gap-detection on a cellular level. (A) Mouse SPN neurons show offset firing in responses to gaps of different durations (60–20 ms) embedded in trains of electrically evoked IPSPs. (B) Bath application of an NO donor reduced the number of action potentials per gap and delayed the action potential within the gap so that only longer gaps were detected. Stimulus artifacts were removed for clarity. (C) The number of evoked action potentials increased with gap duration in controls (black bars), but was never more than one with NO (white bars). (D) Repetitive stimulation (10 IPSP trains) was used to estimate gap-detection success, which is plotted here as % offset action potentials against gap duration. Threshold was defined as 50% success (dashed line); controls (black) reliably detected gaps of 20 ms or longer, but following NO, gap-detection thresholds increased to 60 ms or longer. Data plotted as mean ± s.e.m. (n indicated on the respective graph).

Mentions: SPN neurons receive a range of synaptic projections and express a suite of voltage-gated ionic conductances that enable these neurons to integrate their inputs and fire rebound action potentials at the end of an IPSP train (Kopp-Scheinpflug et al., 2011). This in turn allows computation of auditory gap-detection (Kadner and Berrebi, 2008). We used a gap-detection paradigm to explore how this physiological mechanism is influenced by NO signaling. Gap-detection on a cellular level was determined by current-clamp recording from SPN neurons during synaptic stimulation of the inhibitory inputs from the MNTB. Two 100 Hz stimulus trains of 100 ms duration each were separated by gaps of 20, 30, 40, 50, or 60 ms (each gap-protocol was repeated 10 times). At the gap, short-latency offset action potentials were generated (Figure 7A) in the SPN neurons, with action potential numbers proportional to gap-duration (Figure 7C). In the control condition (low-NO), all gaps evoked action potentials and gaps of 20 ms or longer were reliably detected with success rates greater than 50%. However, following bath application of NO, gap-detection thresholds increased, so that only longer gaps triggered action potentials (Figures 7B,C) and gap-detection for durations shorter than 60 ms was disabled (Figure 7D).


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

Yassin L, Radtke-Schuller S, Asraf H, Grothe B, Hershfinkel M, Forsythe ID, Kopp-Scheinpflug C - Front Neural Circuits (2014)

Nitric oxide suppresses gap-detection on a cellular level. (A) Mouse SPN neurons show offset firing in responses to gaps of different durations (60–20 ms) embedded in trains of electrically evoked IPSPs. (B) Bath application of an NO donor reduced the number of action potentials per gap and delayed the action potential within the gap so that only longer gaps were detected. Stimulus artifacts were removed for clarity. (C) The number of evoked action potentials increased with gap duration in controls (black bars), but was never more than one with NO (white bars). (D) Repetitive stimulation (10 IPSP trains) was used to estimate gap-detection success, which is plotted here as % offset action potentials against gap duration. Threshold was defined as 50% success (dashed line); controls (black) reliably detected gaps of 20 ms or longer, but following NO, gap-detection thresholds increased to 60 ms or longer. Data plotted as mean ± s.e.m. (n indicated on the respective graph).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4060731&req=5

Figure 7: Nitric oxide suppresses gap-detection on a cellular level. (A) Mouse SPN neurons show offset firing in responses to gaps of different durations (60–20 ms) embedded in trains of electrically evoked IPSPs. (B) Bath application of an NO donor reduced the number of action potentials per gap and delayed the action potential within the gap so that only longer gaps were detected. Stimulus artifacts were removed for clarity. (C) The number of evoked action potentials increased with gap duration in controls (black bars), but was never more than one with NO (white bars). (D) Repetitive stimulation (10 IPSP trains) was used to estimate gap-detection success, which is plotted here as % offset action potentials against gap duration. Threshold was defined as 50% success (dashed line); controls (black) reliably detected gaps of 20 ms or longer, but following NO, gap-detection thresholds increased to 60 ms or longer. Data plotted as mean ± s.e.m. (n indicated on the respective graph).
Mentions: SPN neurons receive a range of synaptic projections and express a suite of voltage-gated ionic conductances that enable these neurons to integrate their inputs and fire rebound action potentials at the end of an IPSP train (Kopp-Scheinpflug et al., 2011). This in turn allows computation of auditory gap-detection (Kadner and Berrebi, 2008). We used a gap-detection paradigm to explore how this physiological mechanism is influenced by NO signaling. Gap-detection on a cellular level was determined by current-clamp recording from SPN neurons during synaptic stimulation of the inhibitory inputs from the MNTB. Two 100 Hz stimulus trains of 100 ms duration each were separated by gaps of 20, 30, 40, 50, or 60 ms (each gap-protocol was repeated 10 times). At the gap, short-latency offset action potentials were generated (Figure 7A) in the SPN neurons, with action potential numbers proportional to gap-duration (Figure 7C). In the control condition (low-NO), all gaps evoked action potentials and gaps of 20 ms or longer were reliably detected with success rates greater than 50%. However, following bath application of NO, gap-detection thresholds increased, so that only longer gaps triggered action potentials (Figures 7B,C) and gap-detection for durations shorter than 60 ms was disabled (Figure 7D).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Division of Neurobiology, Department Biology II, Ludwig-Maximilians-University Munich Planegg-Martinsried, Germany.

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).

Show MeSH
Related in: MedlinePlus