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Inhibition of post-synaptic Kv7/KCNQ/M channels facilitates long-term potentiation in the hippocampus.

Petrovic MM, Nowacki J, Olivo V, Tsaneva-Atanasova K, Randall AD, Mellor JR - PLoS ONE (2012)

Bottom Line: Negation of Kv7 channels by XE-991 or dynamic clamp did not enhance synaptic NMDAR activation in response to theta burst synaptic stimulation.Furthermore, the effects of XE-991 were reversed by re-introducing a Kv7-like conductance with dynamic clamp.Thus, during the induction of LTP M(1) mAChRs enhance NMDAR opening by two distinct mechanisms namely inhibition of KCa2 and Kv7 channels.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Centre for Synaptic Plasticity, School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom.

ABSTRACT
Activation of muscarinic acetylcholine receptors (mAChR) facilitates the induction of synaptic plasticity and enhances cognitive function. In the hippocampus, M(1) mAChR on CA1 pyramidal cells inhibit both small conductance Ca(2+)-activated KCa2 potassium channels and voltage-activated Kv7 potassium channels. Inhibition of KCa2 channels facilitates long-term potentiation (LTP) by enhancing Ca(2+)calcium influx through postsynaptic NMDA receptors (NMDAR). Inhibition of Kv7 channels is also reported to facilitate LTP but the mechanism of action is unclear. Here, we show that inhibition of Kv7 channels with XE-991 facilitated LTP induced by theta burst pairing at Schaffer collateral commissural synapses in rat hippocampal slices. Similarly, negating Kv7 channel conductance using dynamic clamp methodologies also facilitated LTP. Negation of Kv7 channels by XE-991 or dynamic clamp did not enhance synaptic NMDAR activation in response to theta burst synaptic stimulation. Instead, Kv7 channel inhibition increased the amplitude and duration of the after-depolarisation following a burst of action potentials. Furthermore, the effects of XE-991 were reversed by re-introducing a Kv7-like conductance with dynamic clamp. These data reveal that Kv7 channel inhibition promotes NMDAR opening during LTP induction by enhancing depolarisation during and after bursts of postsynaptic action potentials. Thus, during the induction of LTP M(1) mAChRs enhance NMDAR opening by two distinct mechanisms namely inhibition of KCa2 and Kv7 channels.

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Injection or removal of Kv7 conductance by dynamic clamp reverses or mimics the effects of XE-991.A) Changes in membrane potential and input resistance caused by introduction of negative dynamic clamp Kv7 conductance (blue bar), XE-991 (10 µM, red bar) and positive dynamic clamp Kv7 conductance (green bar). Example voltage traces show responses to a hyperpolarising current in each condition. B) Left: Negative dynamic clamp Kv7 conductance prolongs the duration of summated EPSPs. Switching the dynamic clamping off completely reversed its effects. Example voltage traces in control (black) or negative dynamic clamp (blue). Middle: XE-991 prolonged the duration of summated EPSPs and this effect was completely reversed by positive dynamic clamp Kv7 conductance. Example voltage traces in control (black), XE-991 (red) and XE-991+Kv7 conductance (green). Right: Average membrane decay time constant shows similar increase in both negative dynamic clamp Kv7 conductance and XE-991. The effect of XE-991 is completely reversed by positive dynamic clamp Kv7 conductance. C) Left: Negative dynamic clamp Kv7 conductance prolonged the membrane decay time constant in response to a short subthreshold current injection. Switching the dynamic clamping off completely reversed its effects. Example voltage traces in control (black) or negative dynamic clamp Kv7 conductance (blue). Middle: XE-991 (red) prolonged the membrane decay time constant compared to control (black) and this effect was completely reversed by positive dynamic clamp Kv7 conductance (green). Right: Average membrane decay time constant shows similar increase in both negative dynamic clamp Kv7 conductance and XE-991. The effect of XE-991 is completely reversed by positive dynamic clamp Kv7 conductance.
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pone-0030402-g003: Injection or removal of Kv7 conductance by dynamic clamp reverses or mimics the effects of XE-991.A) Changes in membrane potential and input resistance caused by introduction of negative dynamic clamp Kv7 conductance (blue bar), XE-991 (10 µM, red bar) and positive dynamic clamp Kv7 conductance (green bar). Example voltage traces show responses to a hyperpolarising current in each condition. B) Left: Negative dynamic clamp Kv7 conductance prolongs the duration of summated EPSPs. Switching the dynamic clamping off completely reversed its effects. Example voltage traces in control (black) or negative dynamic clamp (blue). Middle: XE-991 prolonged the duration of summated EPSPs and this effect was completely reversed by positive dynamic clamp Kv7 conductance. Example voltage traces in control (black), XE-991 (red) and XE-991+Kv7 conductance (green). Right: Average membrane decay time constant shows similar increase in both negative dynamic clamp Kv7 conductance and XE-991. The effect of XE-991 is completely reversed by positive dynamic clamp Kv7 conductance. C) Left: Negative dynamic clamp Kv7 conductance prolonged the membrane decay time constant in response to a short subthreshold current injection. Switching the dynamic clamping off completely reversed its effects. Example voltage traces in control (black) or negative dynamic clamp Kv7 conductance (blue). Middle: XE-991 (red) prolonged the membrane decay time constant compared to control (black) and this effect was completely reversed by positive dynamic clamp Kv7 conductance (green). Right: Average membrane decay time constant shows similar increase in both negative dynamic clamp Kv7 conductance and XE-991. The effect of XE-991 is completely reversed by positive dynamic clamp Kv7 conductance.

Mentions: We next sought to confirm the role of Kv7 like channels in changes to synaptic responses using a dynamic clamp system [33], [44], [45], [46]. This apparatus was used to negate Kv7 conductance and mimic the effect of pharmacological inhibition of Kv7 channels. A model for Kv7 channel voltage dependence and kinetics calculated from experimentally determined values for channels composed of Kv7.2 and Kv7.3 (thought to be the dominant subtypes in CA1 pyramidal cells) was used to parameterize the dynamic clamp system [36], [37], [47], [48] (see methods). To negate existing Kv7 channel activity, the dynamic clamp was used to introduce negative Kv7 conductance to the cell. The amount of conductance was set to generate a depolarisation of ∼2 mV, similar to that produced by pharmacological block of Kv7 channels with XE-991. This also produced an increase in input resistance of 53.6±10.5 MΩ, similar to that produced by XE-991. In each experiment we then switched off the dynamic clamp and applied XE-991 to check that the negation of Kv7 conductance by dynamic clamp and inhibition of Kv7 channels by XE-991 had equivalent effects on membrane potential and input resistance for each cell. Finally, we reversed the effects of XE-991 by using the dynamic clamp system to apply a positive Kv7 conductance with the. This produced a return to baseline values for both membrane potential and input resistance (Figure 3A; ΔVm = 0.06±0.15 mV and ΔRin = 20.3±9.3 MΩ, relative to control values prior to XE-991 application).


Inhibition of post-synaptic Kv7/KCNQ/M channels facilitates long-term potentiation in the hippocampus.

Petrovic MM, Nowacki J, Olivo V, Tsaneva-Atanasova K, Randall AD, Mellor JR - PLoS ONE (2012)

Injection or removal of Kv7 conductance by dynamic clamp reverses or mimics the effects of XE-991.A) Changes in membrane potential and input resistance caused by introduction of negative dynamic clamp Kv7 conductance (blue bar), XE-991 (10 µM, red bar) and positive dynamic clamp Kv7 conductance (green bar). Example voltage traces show responses to a hyperpolarising current in each condition. B) Left: Negative dynamic clamp Kv7 conductance prolongs the duration of summated EPSPs. Switching the dynamic clamping off completely reversed its effects. Example voltage traces in control (black) or negative dynamic clamp (blue). Middle: XE-991 prolonged the duration of summated EPSPs and this effect was completely reversed by positive dynamic clamp Kv7 conductance. Example voltage traces in control (black), XE-991 (red) and XE-991+Kv7 conductance (green). Right: Average membrane decay time constant shows similar increase in both negative dynamic clamp Kv7 conductance and XE-991. The effect of XE-991 is completely reversed by positive dynamic clamp Kv7 conductance. C) Left: Negative dynamic clamp Kv7 conductance prolonged the membrane decay time constant in response to a short subthreshold current injection. Switching the dynamic clamping off completely reversed its effects. Example voltage traces in control (black) or negative dynamic clamp Kv7 conductance (blue). Middle: XE-991 (red) prolonged the membrane decay time constant compared to control (black) and this effect was completely reversed by positive dynamic clamp Kv7 conductance (green). Right: Average membrane decay time constant shows similar increase in both negative dynamic clamp Kv7 conductance and XE-991. The effect of XE-991 is completely reversed by positive dynamic clamp Kv7 conductance.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3278412&req=5

pone-0030402-g003: Injection or removal of Kv7 conductance by dynamic clamp reverses or mimics the effects of XE-991.A) Changes in membrane potential and input resistance caused by introduction of negative dynamic clamp Kv7 conductance (blue bar), XE-991 (10 µM, red bar) and positive dynamic clamp Kv7 conductance (green bar). Example voltage traces show responses to a hyperpolarising current in each condition. B) Left: Negative dynamic clamp Kv7 conductance prolongs the duration of summated EPSPs. Switching the dynamic clamping off completely reversed its effects. Example voltage traces in control (black) or negative dynamic clamp (blue). Middle: XE-991 prolonged the duration of summated EPSPs and this effect was completely reversed by positive dynamic clamp Kv7 conductance. Example voltage traces in control (black), XE-991 (red) and XE-991+Kv7 conductance (green). Right: Average membrane decay time constant shows similar increase in both negative dynamic clamp Kv7 conductance and XE-991. The effect of XE-991 is completely reversed by positive dynamic clamp Kv7 conductance. C) Left: Negative dynamic clamp Kv7 conductance prolonged the membrane decay time constant in response to a short subthreshold current injection. Switching the dynamic clamping off completely reversed its effects. Example voltage traces in control (black) or negative dynamic clamp Kv7 conductance (blue). Middle: XE-991 (red) prolonged the membrane decay time constant compared to control (black) and this effect was completely reversed by positive dynamic clamp Kv7 conductance (green). Right: Average membrane decay time constant shows similar increase in both negative dynamic clamp Kv7 conductance and XE-991. The effect of XE-991 is completely reversed by positive dynamic clamp Kv7 conductance.
Mentions: We next sought to confirm the role of Kv7 like channels in changes to synaptic responses using a dynamic clamp system [33], [44], [45], [46]. This apparatus was used to negate Kv7 conductance and mimic the effect of pharmacological inhibition of Kv7 channels. A model for Kv7 channel voltage dependence and kinetics calculated from experimentally determined values for channels composed of Kv7.2 and Kv7.3 (thought to be the dominant subtypes in CA1 pyramidal cells) was used to parameterize the dynamic clamp system [36], [37], [47], [48] (see methods). To negate existing Kv7 channel activity, the dynamic clamp was used to introduce negative Kv7 conductance to the cell. The amount of conductance was set to generate a depolarisation of ∼2 mV, similar to that produced by pharmacological block of Kv7 channels with XE-991. This also produced an increase in input resistance of 53.6±10.5 MΩ, similar to that produced by XE-991. In each experiment we then switched off the dynamic clamp and applied XE-991 to check that the negation of Kv7 conductance by dynamic clamp and inhibition of Kv7 channels by XE-991 had equivalent effects on membrane potential and input resistance for each cell. Finally, we reversed the effects of XE-991 by using the dynamic clamp system to apply a positive Kv7 conductance with the. This produced a return to baseline values for both membrane potential and input resistance (Figure 3A; ΔVm = 0.06±0.15 mV and ΔRin = 20.3±9.3 MΩ, relative to control values prior to XE-991 application).

Bottom Line: Negation of Kv7 channels by XE-991 or dynamic clamp did not enhance synaptic NMDAR activation in response to theta burst synaptic stimulation.Furthermore, the effects of XE-991 were reversed by re-introducing a Kv7-like conductance with dynamic clamp.Thus, during the induction of LTP M(1) mAChRs enhance NMDAR opening by two distinct mechanisms namely inhibition of KCa2 and Kv7 channels.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Centre for Synaptic Plasticity, School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom.

ABSTRACT
Activation of muscarinic acetylcholine receptors (mAChR) facilitates the induction of synaptic plasticity and enhances cognitive function. In the hippocampus, M(1) mAChR on CA1 pyramidal cells inhibit both small conductance Ca(2+)-activated KCa2 potassium channels and voltage-activated Kv7 potassium channels. Inhibition of KCa2 channels facilitates long-term potentiation (LTP) by enhancing Ca(2+)calcium influx through postsynaptic NMDA receptors (NMDAR). Inhibition of Kv7 channels is also reported to facilitate LTP but the mechanism of action is unclear. Here, we show that inhibition of Kv7 channels with XE-991 facilitated LTP induced by theta burst pairing at Schaffer collateral commissural synapses in rat hippocampal slices. Similarly, negating Kv7 channel conductance using dynamic clamp methodologies also facilitated LTP. Negation of Kv7 channels by XE-991 or dynamic clamp did not enhance synaptic NMDAR activation in response to theta burst synaptic stimulation. Instead, Kv7 channel inhibition increased the amplitude and duration of the after-depolarisation following a burst of action potentials. Furthermore, the effects of XE-991 were reversed by re-introducing a Kv7-like conductance with dynamic clamp. These data reveal that Kv7 channel inhibition promotes NMDAR opening during LTP induction by enhancing depolarisation during and after bursts of postsynaptic action potentials. Thus, during the induction of LTP M(1) mAChRs enhance NMDAR opening by two distinct mechanisms namely inhibition of KCa2 and Kv7 channels.

Show MeSH
Related in: MedlinePlus