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I(h)-mediated depolarization enhances the temporal precision of neuronal integration.

Pavlov I, Scimemi A, Savtchenko L, Kullmann DM, Walker MC - Nat Commun (2011)

Bottom Line: These receptors exert their inhibitory effect by shunting excitatory currents and by hyperpolarizing neurons.In this study, we show that by depolarizing the resting membrane potential relative to the reversal potential for GABA(A) receptors, the hyperpolarization-activated mixed cation current (I(h)) maintains a voltage gradient for fast synaptic inhibition in hippocampal pyramidal cells.These results indicate that the hyperpolarizing component of GABA(A) receptor-mediated inhibition has an important role in maintaining the temporal fidelity of coincidence detection and suggest a previously unrecognized mechanism by which I(h) modulates information processing in the hippocampus.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London WC1N 3GB, UK.

ABSTRACT
Feed-forward inhibition mediated by ionotropic GABA(A) receptors contributes to the temporal precision of neuronal signal integration. These receptors exert their inhibitory effect by shunting excitatory currents and by hyperpolarizing neurons. The relative roles of these mechanisms in neuronal computations are, however, incompletely understood. In this study, we show that by depolarizing the resting membrane potential relative to the reversal potential for GABA(A) receptors, the hyperpolarization-activated mixed cation current (I(h)) maintains a voltage gradient for fast synaptic inhibition in hippocampal pyramidal cells. Pharmacological or genetic ablation of I(h) broadens the depolarizing phase of afferent synaptic waveforms by hyperpolarizing the resting membrane potential. This increases the integration time window for action potential generation. These results indicate that the hyperpolarizing component of GABA(A) receptor-mediated inhibition has an important role in maintaining the temporal fidelity of coincidence detection and suggest a previously unrecognized mechanism by which I(h) modulates information processing in the hippocampus.

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Ih block abolishes the hyperpolarizing phase of the EPSP–IPSP sequence.(a) EPSP–IPSP sequences were evoked in CA1 pyramidal cells by Schaffer collateral stimulation as in Figure 1. Consecutive traces from a representative experiment showing a shift in VR following ZD-7228 application, associated abolition of the GABAA receptor-mediated hyperpolarizing component of the EPSP–IPSP sequence (GABAB receptors are blocked with 5 μM CGP52432) and the overall contribution of inhibition revealed by subsequent application of picrotoxin (PTX). (b) Summary of ZD-7288 effect on EPSP–IPSP characteristics with (direct current (DC)) and without constant current injection to compensate for ZD-7288-induced shift in VR (n=4 cells; shaded columns: ZD-7288, open columns: ZD-7288+DC). Overlapped averaged traces are shown on the left (prepulse baseline is normalized). (c) Effect of application of ZD-7288 on the amplitude and duration of pharmacologically isolated EPSPs, while maintaining VR with current injection (n=7; recordings were made in the presence of 5 μM CGP52432 and 100 μM picrotoxin); this effect is similar to the effect of ZD-7288 on the EPSP–IPSP sequence+DC (b). Bar charts represent percentage change of control values; error bars represent s.e.m.; *P<0.05, **P<0.01, ***P<0.001.
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f2: Ih block abolishes the hyperpolarizing phase of the EPSP–IPSP sequence.(a) EPSP–IPSP sequences were evoked in CA1 pyramidal cells by Schaffer collateral stimulation as in Figure 1. Consecutive traces from a representative experiment showing a shift in VR following ZD-7228 application, associated abolition of the GABAA receptor-mediated hyperpolarizing component of the EPSP–IPSP sequence (GABAB receptors are blocked with 5 μM CGP52432) and the overall contribution of inhibition revealed by subsequent application of picrotoxin (PTX). (b) Summary of ZD-7288 effect on EPSP–IPSP characteristics with (direct current (DC)) and without constant current injection to compensate for ZD-7288-induced shift in VR (n=4 cells; shaded columns: ZD-7288, open columns: ZD-7288+DC). Overlapped averaged traces are shown on the left (prepulse baseline is normalized). (c) Effect of application of ZD-7288 on the amplitude and duration of pharmacologically isolated EPSPs, while maintaining VR with current injection (n=7; recordings were made in the presence of 5 μM CGP52432 and 100 μM picrotoxin); this effect is similar to the effect of ZD-7288 on the EPSP–IPSP sequence+DC (b). Bar charts represent percentage change of control values; error bars represent s.e.m.; *P<0.05, **P<0.01, ***P<0.001.

Mentions: Input summation in the above experiments depends on the time course of the EPSP–IPSP sequence41920. The long membrane time constant of hippocampal principal cells permits EPSP summation over a large time window, but disynaptic feed-forward inhibition limits the temporal summation of the excitatory inputs by curtailing the EPSPs419. Ih could influence the EPSP–IPSP sequence profile by altering membrane conductance2122, interneuron recruitment23 and/or VR91011. To address the relative roles of these effects of Ih, we evoked an EPSP–IPSP sequence in CA1 pyramidal cells by stimulating Schaffer collaterals, and then blocked Ih with and without correcting the membrane voltage (Fig. 2). Blocking Ih with ZD-7288 completely abolished the hyperpolarizing component of the EPSP–IPSP sequence and resulted in considerable broadening of the half-width of the depolarizing phase of the response to 251±27% of control (n=4; P=0.003; Fig. 2a,b).


I(h)-mediated depolarization enhances the temporal precision of neuronal integration.

Pavlov I, Scimemi A, Savtchenko L, Kullmann DM, Walker MC - Nat Commun (2011)

Ih block abolishes the hyperpolarizing phase of the EPSP–IPSP sequence.(a) EPSP–IPSP sequences were evoked in CA1 pyramidal cells by Schaffer collateral stimulation as in Figure 1. Consecutive traces from a representative experiment showing a shift in VR following ZD-7228 application, associated abolition of the GABAA receptor-mediated hyperpolarizing component of the EPSP–IPSP sequence (GABAB receptors are blocked with 5 μM CGP52432) and the overall contribution of inhibition revealed by subsequent application of picrotoxin (PTX). (b) Summary of ZD-7288 effect on EPSP–IPSP characteristics with (direct current (DC)) and without constant current injection to compensate for ZD-7288-induced shift in VR (n=4 cells; shaded columns: ZD-7288, open columns: ZD-7288+DC). Overlapped averaged traces are shown on the left (prepulse baseline is normalized). (c) Effect of application of ZD-7288 on the amplitude and duration of pharmacologically isolated EPSPs, while maintaining VR with current injection (n=7; recordings were made in the presence of 5 μM CGP52432 and 100 μM picrotoxin); this effect is similar to the effect of ZD-7288 on the EPSP–IPSP sequence+DC (b). Bar charts represent percentage change of control values; error bars represent s.e.m.; *P<0.05, **P<0.01, ***P<0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3105342&req=5

f2: Ih block abolishes the hyperpolarizing phase of the EPSP–IPSP sequence.(a) EPSP–IPSP sequences were evoked in CA1 pyramidal cells by Schaffer collateral stimulation as in Figure 1. Consecutive traces from a representative experiment showing a shift in VR following ZD-7228 application, associated abolition of the GABAA receptor-mediated hyperpolarizing component of the EPSP–IPSP sequence (GABAB receptors are blocked with 5 μM CGP52432) and the overall contribution of inhibition revealed by subsequent application of picrotoxin (PTX). (b) Summary of ZD-7288 effect on EPSP–IPSP characteristics with (direct current (DC)) and without constant current injection to compensate for ZD-7288-induced shift in VR (n=4 cells; shaded columns: ZD-7288, open columns: ZD-7288+DC). Overlapped averaged traces are shown on the left (prepulse baseline is normalized). (c) Effect of application of ZD-7288 on the amplitude and duration of pharmacologically isolated EPSPs, while maintaining VR with current injection (n=7; recordings were made in the presence of 5 μM CGP52432 and 100 μM picrotoxin); this effect is similar to the effect of ZD-7288 on the EPSP–IPSP sequence+DC (b). Bar charts represent percentage change of control values; error bars represent s.e.m.; *P<0.05, **P<0.01, ***P<0.001.
Mentions: Input summation in the above experiments depends on the time course of the EPSP–IPSP sequence41920. The long membrane time constant of hippocampal principal cells permits EPSP summation over a large time window, but disynaptic feed-forward inhibition limits the temporal summation of the excitatory inputs by curtailing the EPSPs419. Ih could influence the EPSP–IPSP sequence profile by altering membrane conductance2122, interneuron recruitment23 and/or VR91011. To address the relative roles of these effects of Ih, we evoked an EPSP–IPSP sequence in CA1 pyramidal cells by stimulating Schaffer collaterals, and then blocked Ih with and without correcting the membrane voltage (Fig. 2). Blocking Ih with ZD-7288 completely abolished the hyperpolarizing component of the EPSP–IPSP sequence and resulted in considerable broadening of the half-width of the depolarizing phase of the response to 251±27% of control (n=4; P=0.003; Fig. 2a,b).

Bottom Line: These receptors exert their inhibitory effect by shunting excitatory currents and by hyperpolarizing neurons.In this study, we show that by depolarizing the resting membrane potential relative to the reversal potential for GABA(A) receptors, the hyperpolarization-activated mixed cation current (I(h)) maintains a voltage gradient for fast synaptic inhibition in hippocampal pyramidal cells.These results indicate that the hyperpolarizing component of GABA(A) receptor-mediated inhibition has an important role in maintaining the temporal fidelity of coincidence detection and suggest a previously unrecognized mechanism by which I(h) modulates information processing in the hippocampus.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London WC1N 3GB, UK.

ABSTRACT
Feed-forward inhibition mediated by ionotropic GABA(A) receptors contributes to the temporal precision of neuronal signal integration. These receptors exert their inhibitory effect by shunting excitatory currents and by hyperpolarizing neurons. The relative roles of these mechanisms in neuronal computations are, however, incompletely understood. In this study, we show that by depolarizing the resting membrane potential relative to the reversal potential for GABA(A) receptors, the hyperpolarization-activated mixed cation current (I(h)) maintains a voltage gradient for fast synaptic inhibition in hippocampal pyramidal cells. Pharmacological or genetic ablation of I(h) broadens the depolarizing phase of afferent synaptic waveforms by hyperpolarizing the resting membrane potential. This increases the integration time window for action potential generation. These results indicate that the hyperpolarizing component of GABA(A) receptor-mediated inhibition has an important role in maintaining the temporal fidelity of coincidence detection and suggest a previously unrecognized mechanism by which I(h) modulates information processing in the hippocampus.

Show MeSH
Related in: MedlinePlus