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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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The effects of changing the magnitude of inhibitory conductances on the width of the integration time window.(a) In the absence of feed-forward inhibition (no IPSPs), the integration time window became broader. Under such conditions, membrane hyperpolarization did not change the width of coincidence detection, indicating that changes in the polarizing effect of GABAA receptor-mediated currents, rather than the VR value itself, determine neuronal integration (open bars: Vm=−70 mV no IPSP; hatched bars: Vm=−80 mV no IPSP; red bars: Vm=−70 mV with IPSP). (b) The effect of varying the strength of inhibitory connections on the width of the integration time window assessed as the change in the area under the spike probability curve (AUC). (c) The effect of hyperpolarization on the coincidence-detection time window when inhibitory synaptic conductances were scaled with excitatory conductances, mimicking the situation when inhibitory inputs onto a neuron are not saturated. Data are presented as means of 30 rounds of simulations, error bars represent s.e.m.; *P<0.05, **P<0.01, ***P<0.001.
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f7: The effects of changing the magnitude of inhibitory conductances on the width of the integration time window.(a) In the absence of feed-forward inhibition (no IPSPs), the integration time window became broader. Under such conditions, membrane hyperpolarization did not change the width of coincidence detection, indicating that changes in the polarizing effect of GABAA receptor-mediated currents, rather than the VR value itself, determine neuronal integration (open bars: Vm=−70 mV no IPSP; hatched bars: Vm=−80 mV no IPSP; red bars: Vm=−70 mV with IPSP). (b) The effect of varying the strength of inhibitory connections on the width of the integration time window assessed as the change in the area under the spike probability curve (AUC). (c) The effect of hyperpolarization on the coincidence-detection time window when inhibitory synaptic conductances were scaled with excitatory conductances, mimicking the situation when inhibitory inputs onto a neuron are not saturated. Data are presented as means of 30 rounds of simulations, error bars represent s.e.m.; *P<0.05, **P<0.01, ***P<0.001.

Mentions: We next asked whether the effect that we observed was due to the voltage change itself rather than the change in the polarity of GABAA receptor-mediated transmission. We therefore assessed the effects of membrane potential on the integration time window in the absence of GABAergic transmission. As expected4, removing feed-forward inhibition broadened the integration time window by 106.8±6.7%. However, the width of the window was minimally affected by changes in VR in the range observed in our experiments and simulations (Fig. 7a; an increase of 3.1±0.4% with 10 mV hyperpolarization).


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

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

The effects of changing the magnitude of inhibitory conductances on the width of the integration time window.(a) In the absence of feed-forward inhibition (no IPSPs), the integration time window became broader. Under such conditions, membrane hyperpolarization did not change the width of coincidence detection, indicating that changes in the polarizing effect of GABAA receptor-mediated currents, rather than the VR value itself, determine neuronal integration (open bars: Vm=−70 mV no IPSP; hatched bars: Vm=−80 mV no IPSP; red bars: Vm=−70 mV with IPSP). (b) The effect of varying the strength of inhibitory connections on the width of the integration time window assessed as the change in the area under the spike probability curve (AUC). (c) The effect of hyperpolarization on the coincidence-detection time window when inhibitory synaptic conductances were scaled with excitatory conductances, mimicking the situation when inhibitory inputs onto a neuron are not saturated. Data are presented as means of 30 rounds of simulations, error bars represent s.e.m.; *P<0.05, **P<0.01, ***P<0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7: The effects of changing the magnitude of inhibitory conductances on the width of the integration time window.(a) In the absence of feed-forward inhibition (no IPSPs), the integration time window became broader. Under such conditions, membrane hyperpolarization did not change the width of coincidence detection, indicating that changes in the polarizing effect of GABAA receptor-mediated currents, rather than the VR value itself, determine neuronal integration (open bars: Vm=−70 mV no IPSP; hatched bars: Vm=−80 mV no IPSP; red bars: Vm=−70 mV with IPSP). (b) The effect of varying the strength of inhibitory connections on the width of the integration time window assessed as the change in the area under the spike probability curve (AUC). (c) The effect of hyperpolarization on the coincidence-detection time window when inhibitory synaptic conductances were scaled with excitatory conductances, mimicking the situation when inhibitory inputs onto a neuron are not saturated. Data are presented as means of 30 rounds of simulations, error bars represent s.e.m.; *P<0.05, **P<0.01, ***P<0.001.
Mentions: We next asked whether the effect that we observed was due to the voltage change itself rather than the change in the polarity of GABAA receptor-mediated transmission. We therefore assessed the effects of membrane potential on the integration time window in the absence of GABAergic transmission. As expected4, removing feed-forward inhibition broadened the integration time window by 106.8±6.7%. However, the width of the window was minimally affected by changes in VR in the range observed in our experiments and simulations (Fig. 7a; an increase of 3.1±0.4% with 10 mV hyperpolarization).

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