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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-mediated hyperpolarization broadens the integration time window in an integrate-and-fire neuronal model.(a) Successive activation of excitatory and inhibitory conductances in a simple integrate-and-fire neuron was used to produce an EPSP–IPSP sequence similar to that observed experimentally. (b) Simulation of two pathways activated with different delays (see Methods) resulted in a narrow integration time window. Synaptic strength was adjusted so that the peak probability of action potential generation remained at 50%. (c) Removal of Ih from the dendrites hyperpolarized the modelled neuron by 10 mV. The graph shows spike probability at different intervals between stimuli with (open bars) and without Ih (red bars) in the modelled neuron. (d) The effect of Ih removal was abolished when the neuronal soma was repolarized by DC injection (open bars: control with Ih, blue bars: no Ih repolarized). Data are presented as means of 30 rounds of simulations, error bars represent s.e.m.
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f6: Ih-mediated hyperpolarization broadens the integration time window in an integrate-and-fire neuronal model.(a) Successive activation of excitatory and inhibitory conductances in a simple integrate-and-fire neuron was used to produce an EPSP–IPSP sequence similar to that observed experimentally. (b) Simulation of two pathways activated with different delays (see Methods) resulted in a narrow integration time window. Synaptic strength was adjusted so that the peak probability of action potential generation remained at 50%. (c) Removal of Ih from the dendrites hyperpolarized the modelled neuron by 10 mV. The graph shows spike probability at different intervals between stimuli with (open bars) and without Ih (red bars) in the modelled neuron. (d) The effect of Ih removal was abolished when the neuronal soma was repolarized by DC injection (open bars: control with Ih, blue bars: no Ih repolarized). Data are presented as means of 30 rounds of simulations, error bars represent s.e.m.

Mentions: A possible confounder in the above experiments is that in order to maintain a 50% spiking probability, we had to adjust the stimulation intensity to compensate for the membrane hyperpolarization, potentially affecting interneuron recruitment. This would tend to increase the interneuron recruitment and therefore would be expected to narrow the integration time window (in contrast to the broadening that we observed). Nevertheless, to control for this and to address the question of whether loss of the hyperpolarization effect of GABAA receptor currents is sufficient to explain our results, we constructed a simple integrate-and-fire model of a neuron that receives two inputs. Each input consisted of an excitatory followed by an inhibitory conductance, and the parameters were adjusted to simulate the kinetics of the experimentally obtained EPSP–IPSP sequence waveform (see Methods; Fig. 6a). In agreement with the experimental findings, systematic variation of the delay between the two inputs revealed a narrow integration time window for spike generation (Fig. 6b).


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-mediated hyperpolarization broadens the integration time window in an integrate-and-fire neuronal model.(a) Successive activation of excitatory and inhibitory conductances in a simple integrate-and-fire neuron was used to produce an EPSP–IPSP sequence similar to that observed experimentally. (b) Simulation of two pathways activated with different delays (see Methods) resulted in a narrow integration time window. Synaptic strength was adjusted so that the peak probability of action potential generation remained at 50%. (c) Removal of Ih from the dendrites hyperpolarized the modelled neuron by 10 mV. The graph shows spike probability at different intervals between stimuli with (open bars) and without Ih (red bars) in the modelled neuron. (d) The effect of Ih removal was abolished when the neuronal soma was repolarized by DC injection (open bars: control with Ih, blue bars: no Ih repolarized). Data are presented as means of 30 rounds of simulations, error bars represent s.e.m.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: Ih-mediated hyperpolarization broadens the integration time window in an integrate-and-fire neuronal model.(a) Successive activation of excitatory and inhibitory conductances in a simple integrate-and-fire neuron was used to produce an EPSP–IPSP sequence similar to that observed experimentally. (b) Simulation of two pathways activated with different delays (see Methods) resulted in a narrow integration time window. Synaptic strength was adjusted so that the peak probability of action potential generation remained at 50%. (c) Removal of Ih from the dendrites hyperpolarized the modelled neuron by 10 mV. The graph shows spike probability at different intervals between stimuli with (open bars) and without Ih (red bars) in the modelled neuron. (d) The effect of Ih removal was abolished when the neuronal soma was repolarized by DC injection (open bars: control with Ih, blue bars: no Ih repolarized). Data are presented as means of 30 rounds of simulations, error bars represent s.e.m.
Mentions: A possible confounder in the above experiments is that in order to maintain a 50% spiking probability, we had to adjust the stimulation intensity to compensate for the membrane hyperpolarization, potentially affecting interneuron recruitment. This would tend to increase the interneuron recruitment and therefore would be expected to narrow the integration time window (in contrast to the broadening that we observed). Nevertheless, to control for this and to address the question of whether loss of the hyperpolarization effect of GABAA receptor currents is sufficient to explain our results, we constructed a simple integrate-and-fire model of a neuron that receives two inputs. Each input consisted of an excitatory followed by an inhibitory conductance, and the parameters were adjusted to simulate the kinetics of the experimentally obtained EPSP–IPSP sequence waveform (see Methods; Fig. 6a). In agreement with the experimental findings, systematic variation of the delay between the two inputs revealed a narrow integration time window for spike generation (Fig. 6b).

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