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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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Block of Ih widens the coincidence-detection time window.(a) Two Schaffer collateral pathways (St.1 and St.2) were stimulated on either side of the recorded neuron ∼300 μm away from the soma to evoke EPSP–IPSP sequences. (b) Both pathways were then activated at different interstimulus intervals. Traces show sample responses. Stimulation intensities were adjusted so that the probability of evoking action potential was 50% when the two stimuli were delivered simultaneously. (c) Summary graph of probability of evoking an action potential against the interval between stimulations (n=19). (d) Sample experiment demonstrating a change in the coincidence-detection time window following Ih blockade with ZD-7288. Top: Sample traces recorded in response to stimulation of two pathways in control and after application of ZD-7288; middle: raster plots of spike generation; bottom: frequency histograms showing spike probability at different intervals between stimuli. (e) Summary graph of relative probability of firing at different interstimulus intervals in control conditions (open columns) and in the presence of ZD-7288 (shaded columns; n=6; P=0.011 for difference). (f) The probability of evoking an action potential by simultaneous activation of both pathways under baseline conditions and after the readjustment of stimulus intensity following Ih block (open circles: individual recordings; closed circles: averaged data; n=6). Error bars represent s.e.m.
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f1: Block of Ih widens the coincidence-detection time window.(a) Two Schaffer collateral pathways (St.1 and St.2) were stimulated on either side of the recorded neuron ∼300 μm away from the soma to evoke EPSP–IPSP sequences. (b) Both pathways were then activated at different interstimulus intervals. Traces show sample responses. Stimulation intensities were adjusted so that the probability of evoking action potential was 50% when the two stimuli were delivered simultaneously. (c) Summary graph of probability of evoking an action potential against the interval between stimulations (n=19). (d) Sample experiment demonstrating a change in the coincidence-detection time window following Ih blockade with ZD-7288. Top: Sample traces recorded in response to stimulation of two pathways in control and after application of ZD-7288; middle: raster plots of spike generation; bottom: frequency histograms showing spike probability at different intervals between stimuli. (e) Summary graph of relative probability of firing at different interstimulus intervals in control conditions (open columns) and in the presence of ZD-7288 (shaded columns; n=6; P=0.011 for difference). (f) The probability of evoking an action potential by simultaneous activation of both pathways under baseline conditions and after the readjustment of stimulus intensity following Ih block (open circles: individual recordings; closed circles: averaged data; n=6). Error bars represent s.e.m.

Mentions: We assessed coincidence detection by recording from CA1 pyramidal cells using gramicidin perforated-patch in current-clamp mode19. We stimulated two separate populations of Schaffer collaterals (Fig. 1a) representing weak and strong synaptic inputs (see Methods). The stimulus intensities were adjusted so that simultaneous activation of the two pathways resulted approximately in a 50% chance of the neuron spiking. We then measured the spike probability while systematically varying the interstimulus interval. As previously reported, the spike probability decreased as the interval increased (Fig. 1b,c). We used 10 μM ZD-7288 to block Ih. Again consistent with previous studies910, this resulted in a hyperpolarization, an increase in input resistance and complete disappearance of the characteristic depolarizing sag of the membrane potential following a hyperpolarizing step current injection (Supplementary Fig. S1). We then readjusted the stimulation intensities to match the spiking probability for simultaneous stimulation observed under control conditions. Blocking Ih resulted in a significant broadening of the time window for integration of the two input stimuli (Fig. 1d–f; n=6; repeated measures analysis of variance (ANOVA): F (1,5)=15.5, P=0.011). We further confirmed this effect using cell-attached recordings at near physiological temperature and with the same stimulation paradigm (Supplementary Fig. S2; n=4; repeated measures ANOVA: F(1,3)=37.3, P=0.009 for the effect of ZD-7288).


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

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

Block of Ih widens the coincidence-detection time window.(a) Two Schaffer collateral pathways (St.1 and St.2) were stimulated on either side of the recorded neuron ∼300 μm away from the soma to evoke EPSP–IPSP sequences. (b) Both pathways were then activated at different interstimulus intervals. Traces show sample responses. Stimulation intensities were adjusted so that the probability of evoking action potential was 50% when the two stimuli were delivered simultaneously. (c) Summary graph of probability of evoking an action potential against the interval between stimulations (n=19). (d) Sample experiment demonstrating a change in the coincidence-detection time window following Ih blockade with ZD-7288. Top: Sample traces recorded in response to stimulation of two pathways in control and after application of ZD-7288; middle: raster plots of spike generation; bottom: frequency histograms showing spike probability at different intervals between stimuli. (e) Summary graph of relative probability of firing at different interstimulus intervals in control conditions (open columns) and in the presence of ZD-7288 (shaded columns; n=6; P=0.011 for difference). (f) The probability of evoking an action potential by simultaneous activation of both pathways under baseline conditions and after the readjustment of stimulus intensity following Ih block (open circles: individual recordings; closed circles: averaged data; n=6). Error bars represent s.e.m.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3105342&req=5

f1: Block of Ih widens the coincidence-detection time window.(a) Two Schaffer collateral pathways (St.1 and St.2) were stimulated on either side of the recorded neuron ∼300 μm away from the soma to evoke EPSP–IPSP sequences. (b) Both pathways were then activated at different interstimulus intervals. Traces show sample responses. Stimulation intensities were adjusted so that the probability of evoking action potential was 50% when the two stimuli were delivered simultaneously. (c) Summary graph of probability of evoking an action potential against the interval between stimulations (n=19). (d) Sample experiment demonstrating a change in the coincidence-detection time window following Ih blockade with ZD-7288. Top: Sample traces recorded in response to stimulation of two pathways in control and after application of ZD-7288; middle: raster plots of spike generation; bottom: frequency histograms showing spike probability at different intervals between stimuli. (e) Summary graph of relative probability of firing at different interstimulus intervals in control conditions (open columns) and in the presence of ZD-7288 (shaded columns; n=6; P=0.011 for difference). (f) The probability of evoking an action potential by simultaneous activation of both pathways under baseline conditions and after the readjustment of stimulus intensity following Ih block (open circles: individual recordings; closed circles: averaged data; n=6). Error bars represent s.e.m.
Mentions: We assessed coincidence detection by recording from CA1 pyramidal cells using gramicidin perforated-patch in current-clamp mode19. We stimulated two separate populations of Schaffer collaterals (Fig. 1a) representing weak and strong synaptic inputs (see Methods). The stimulus intensities were adjusted so that simultaneous activation of the two pathways resulted approximately in a 50% chance of the neuron spiking. We then measured the spike probability while systematically varying the interstimulus interval. As previously reported, the spike probability decreased as the interval increased (Fig. 1b,c). We used 10 μM ZD-7288 to block Ih. Again consistent with previous studies910, this resulted in a hyperpolarization, an increase in input resistance and complete disappearance of the characteristic depolarizing sag of the membrane potential following a hyperpolarizing step current injection (Supplementary Fig. S1). We then readjusted the stimulation intensities to match the spiking probability for simultaneous stimulation observed under control conditions. Blocking Ih resulted in a significant broadening of the time window for integration of the two input stimuli (Fig. 1d–f; n=6; repeated measures analysis of variance (ANOVA): F (1,5)=15.5, P=0.011). We further confirmed this effect using cell-attached recordings at near physiological temperature and with the same stimulation paradigm (Supplementary Fig. S2; n=4; repeated measures ANOVA: F(1,3)=37.3, P=0.009 for the effect of ZD-7288).

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