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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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Repolarization restores temporal precision when Ih is blocked.(a) Spike probability at different intervals between stimuli in control conditions and in the presence of ZD-7288 when neurons were repolarized to their initial VR by DC injection, therefore restoring the biphasic shape of the EPSP–IPSP sequence. Top: sample traces; middle: raster plots of spikes initiated by stimulation of the two pathways at different delay intervals; bottom: spike probability distribution graphs. (b) Averaged data from five experiments (open columns: control, shaded columns: ZD-7288+DC; P=0.57). (c) Probability of action potential generation for synchronous stimulation of both pathways before and after application of ZD-7288 (n=5). Error bars represent s.e.m.
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f5: Repolarization restores temporal precision when Ih is blocked.(a) Spike probability at different intervals between stimuli in control conditions and in the presence of ZD-7288 when neurons were repolarized to their initial VR by DC injection, therefore restoring the biphasic shape of the EPSP–IPSP sequence. Top: sample traces; middle: raster plots of spikes initiated by stimulation of the two pathways at different delay intervals; bottom: spike probability distribution graphs. (b) Averaged data from five experiments (open columns: control, shaded columns: ZD-7288+DC; P=0.57). (c) Probability of action potential generation for synchronous stimulation of both pathways before and after application of ZD-7288 (n=5). Error bars represent s.e.m.

Mentions: Although the broadening of input integration is consistent with the hypothesis that GABAA receptor-mediated hyperpolarization is required to maintain the narrow time window for coincidence detection, an alternative potential explanation is that Ih has a profound effect upon dendritic excitability and temporal summation of excitatory inputs1213. To distinguish between these hypotheses, we repeated the coincidence-detection experiments, but depolarized the neuron following addition of ZD-7288 to return the resting membrane potential to the baseline level. Using this protocol, we observed no change in the time window for integration (Fig. 5; n=5; repeated measures ANOVA: F (1,4)=0.374, P=0.57). This implies that it is primarily the depolarizing effect of Ih and loss of the hyperpolarizing effect of GABAA receptor currents that maintains the narrow coincidence detection for input integration. A further prediction from this is that simple hyperpolarization with Ih intact would widen the coincidence-detection time window, which is indeed the case (n=5, repeated measures ANOVA: F(1,4)=8.2, P=0.046; Supplementary Fig. S3).


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

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

Repolarization restores temporal precision when Ih is blocked.(a) Spike probability at different intervals between stimuli in control conditions and in the presence of ZD-7288 when neurons were repolarized to their initial VR by DC injection, therefore restoring the biphasic shape of the EPSP–IPSP sequence. Top: sample traces; middle: raster plots of spikes initiated by stimulation of the two pathways at different delay intervals; bottom: spike probability distribution graphs. (b) Averaged data from five experiments (open columns: control, shaded columns: ZD-7288+DC; P=0.57). (c) Probability of action potential generation for synchronous stimulation of both pathways before and after application of ZD-7288 (n=5). Error bars represent s.e.m.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: Repolarization restores temporal precision when Ih is blocked.(a) Spike probability at different intervals between stimuli in control conditions and in the presence of ZD-7288 when neurons were repolarized to their initial VR by DC injection, therefore restoring the biphasic shape of the EPSP–IPSP sequence. Top: sample traces; middle: raster plots of spikes initiated by stimulation of the two pathways at different delay intervals; bottom: spike probability distribution graphs. (b) Averaged data from five experiments (open columns: control, shaded columns: ZD-7288+DC; P=0.57). (c) Probability of action potential generation for synchronous stimulation of both pathways before and after application of ZD-7288 (n=5). Error bars represent s.e.m.
Mentions: Although the broadening of input integration is consistent with the hypothesis that GABAA receptor-mediated hyperpolarization is required to maintain the narrow time window for coincidence detection, an alternative potential explanation is that Ih has a profound effect upon dendritic excitability and temporal summation of excitatory inputs1213. To distinguish between these hypotheses, we repeated the coincidence-detection experiments, but depolarized the neuron following addition of ZD-7288 to return the resting membrane potential to the baseline level. Using this protocol, we observed no change in the time window for integration (Fig. 5; n=5; repeated measures ANOVA: F (1,4)=0.374, P=0.57). This implies that it is primarily the depolarizing effect of Ih and loss of the hyperpolarizing effect of GABAA receptor currents that maintains the narrow coincidence detection for input integration. A further prediction from this is that simple hyperpolarization with Ih intact would widen the coincidence-detection time window, which is indeed the case (n=5, repeated measures ANOVA: F(1,4)=8.2, P=0.046; Supplementary Fig. S3).

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