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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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XE-991 does not enhance the NMDAR-mediated component of EPSPs.A) XE-991 (10 µM) depolarised the membrane potential and B) increased input resistance. Example voltage traces show response to a hyperpolarising current in control (black), XE-991 (red), after repolarisation and traces overlaid. Graphs illustrate the timecourse of a single experiment. C) Summated EPSPs during synaptic theta burst stimulation have a small NMDAR-mediated component. Example voltage traces show a burst of five EPSPs under control conditions (black) and in the presence of 50 µM D-AP5 (green). The average normalised decay time constant for a burst of five EPSPs is reduced in the presence of D-AP5. D) XE-991 prolonged the duration of single EPSPs. Example voltage traces in control (black) and XE-991 (red). Average decay time constants increase after application of XE-991. E) XE-991 prolonged the duration of summated EPSPs which was partially reversed either by repolarisation or application of D-AP5. Example voltage traces in control (black), XE-991 (red), XE-991 repolarised (dark red), XE-991 and D-AP5 (green) or XE-991 and D-AP5 repolarised (dark green). Average decay time constants show a partial reversal of EPSP prolongation by D-AP5 at both depolarised and repolarised potentials. F) The effect of D-AP5 on the decay time constant of summated EPSPs was similar in control conditions and in the presence of XE-991. G) XE-991 prolonged the membrane decay time constant in response to a short subthreshold current injection. Example voltage traces in control (black) or XE-991 (red). Average membrane decay time constant shows an increase in XE-991.
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pone-0030402-g002: XE-991 does not enhance the NMDAR-mediated component of EPSPs.A) XE-991 (10 µM) depolarised the membrane potential and B) increased input resistance. Example voltage traces show response to a hyperpolarising current in control (black), XE-991 (red), after repolarisation and traces overlaid. Graphs illustrate the timecourse of a single experiment. C) Summated EPSPs during synaptic theta burst stimulation have a small NMDAR-mediated component. Example voltage traces show a burst of five EPSPs under control conditions (black) and in the presence of 50 µM D-AP5 (green). The average normalised decay time constant for a burst of five EPSPs is reduced in the presence of D-AP5. D) XE-991 prolonged the duration of single EPSPs. Example voltage traces in control (black) and XE-991 (red). Average decay time constants increase after application of XE-991. E) XE-991 prolonged the duration of summated EPSPs which was partially reversed either by repolarisation or application of D-AP5. Example voltage traces in control (black), XE-991 (red), XE-991 repolarised (dark red), XE-991 and D-AP5 (green) or XE-991 and D-AP5 repolarised (dark green). Average decay time constants show a partial reversal of EPSP prolongation by D-AP5 at both depolarised and repolarised potentials. F) The effect of D-AP5 on the decay time constant of summated EPSPs was similar in control conditions and in the presence of XE-991. G) XE-991 prolonged the membrane decay time constant in response to a short subthreshold current injection. Example voltage traces in control (black) or XE-991 (red). Average membrane decay time constant shows an increase in XE-991.

Mentions: Kv7 channels are voltage-dependent potassium channels that contribute to the resting membrane potential of CA1 pyramidal cells and are found primarily on perisomatic membranes [39], [40]. Inhibition of Kv7 channels typically depolarises hippocampal pyramidal neurons and increases their input resistance [26], [27], [41]. In current clamp mode, bath application of 10 µM XE-991 caused a depolarisation of 2.2±0.4 mV (Figure 2A; n = 6, p<0.05) and an increase in input resistance of 53.8±9.6 MΩ (Figure 2B; n = 6, p<0.05). The mean initial resting membrane potential and input resistance were −72.2±1.3 mV and 282.3±31.4 MΩ, respectively (n = 6).


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)

XE-991 does not enhance the NMDAR-mediated component of EPSPs.A) XE-991 (10 µM) depolarised the membrane potential and B) increased input resistance. Example voltage traces show response to a hyperpolarising current in control (black), XE-991 (red), after repolarisation and traces overlaid. Graphs illustrate the timecourse of a single experiment. C) Summated EPSPs during synaptic theta burst stimulation have a small NMDAR-mediated component. Example voltage traces show a burst of five EPSPs under control conditions (black) and in the presence of 50 µM D-AP5 (green). The average normalised decay time constant for a burst of five EPSPs is reduced in the presence of D-AP5. D) XE-991 prolonged the duration of single EPSPs. Example voltage traces in control (black) and XE-991 (red). Average decay time constants increase after application of XE-991. E) XE-991 prolonged the duration of summated EPSPs which was partially reversed either by repolarisation or application of D-AP5. Example voltage traces in control (black), XE-991 (red), XE-991 repolarised (dark red), XE-991 and D-AP5 (green) or XE-991 and D-AP5 repolarised (dark green). Average decay time constants show a partial reversal of EPSP prolongation by D-AP5 at both depolarised and repolarised potentials. F) The effect of D-AP5 on the decay time constant of summated EPSPs was similar in control conditions and in the presence of XE-991. G) XE-991 prolonged the membrane decay time constant in response to a short subthreshold current injection. Example voltage traces in control (black) or XE-991 (red). Average membrane decay time constant shows an increase in XE-991.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3278412&req=5

pone-0030402-g002: XE-991 does not enhance the NMDAR-mediated component of EPSPs.A) XE-991 (10 µM) depolarised the membrane potential and B) increased input resistance. Example voltage traces show response to a hyperpolarising current in control (black), XE-991 (red), after repolarisation and traces overlaid. Graphs illustrate the timecourse of a single experiment. C) Summated EPSPs during synaptic theta burst stimulation have a small NMDAR-mediated component. Example voltage traces show a burst of five EPSPs under control conditions (black) and in the presence of 50 µM D-AP5 (green). The average normalised decay time constant for a burst of five EPSPs is reduced in the presence of D-AP5. D) XE-991 prolonged the duration of single EPSPs. Example voltage traces in control (black) and XE-991 (red). Average decay time constants increase after application of XE-991. E) XE-991 prolonged the duration of summated EPSPs which was partially reversed either by repolarisation or application of D-AP5. Example voltage traces in control (black), XE-991 (red), XE-991 repolarised (dark red), XE-991 and D-AP5 (green) or XE-991 and D-AP5 repolarised (dark green). Average decay time constants show a partial reversal of EPSP prolongation by D-AP5 at both depolarised and repolarised potentials. F) The effect of D-AP5 on the decay time constant of summated EPSPs was similar in control conditions and in the presence of XE-991. G) XE-991 prolonged the membrane decay time constant in response to a short subthreshold current injection. Example voltage traces in control (black) or XE-991 (red). Average membrane decay time constant shows an increase in XE-991.
Mentions: Kv7 channels are voltage-dependent potassium channels that contribute to the resting membrane potential of CA1 pyramidal cells and are found primarily on perisomatic membranes [39], [40]. Inhibition of Kv7 channels typically depolarises hippocampal pyramidal neurons and increases their input resistance [26], [27], [41]. In current clamp mode, bath application of 10 µM XE-991 caused a depolarisation of 2.2±0.4 mV (Figure 2A; n = 6, p<0.05) and an increase in input resistance of 53.8±9.6 MΩ (Figure 2B; n = 6, p<0.05). The mean initial resting membrane potential and input resistance were −72.2±1.3 mV and 282.3±31.4 MΩ, respectively (n = 6).

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