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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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HCN1 deletion results in the loss of the hyperpolarizing effects of GABAA receptor-mediated inhibition.(a) Example traces showing voltage responses to current steps injections in wild-type (WT) mice and HCN1 knockout (KO) mice. (b) An example plot showing that, unlike WT mice, HCN1 KO mice lacked a hyperpolarizing GABAA receptor-mediated driving force. Data points were fitted with a second-order polynomial function. (c) Comparison of VR in HCN1 KO mice and WT mice (WT: n=5; KO: n=8). (d) Summary plot of EGABA(A) in both genotypes (WT: n=5; KO: n=4). (e) Sample traces showing that the KO mice displayed no hyperpolarizing phase at VR, whereas WT animals had a biphasic EPSP–IPSP sequence. The hyperpolarizing IPSPs became apparent in the KO mice when cells were depolarized by DC injection. Conversely, the IPSP was less evident when pyramidal cells from WT mice were hyperpolarized. Error bars represent s.e.m.; **P<0.01.
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f3: HCN1 deletion results in the loss of the hyperpolarizing effects of GABAA receptor-mediated inhibition.(a) Example traces showing voltage responses to current steps injections in wild-type (WT) mice and HCN1 knockout (KO) mice. (b) An example plot showing that, unlike WT mice, HCN1 KO mice lacked a hyperpolarizing GABAA receptor-mediated driving force. Data points were fitted with a second-order polynomial function. (c) Comparison of VR in HCN1 KO mice and WT mice (WT: n=5; KO: n=8). (d) Summary plot of EGABA(A) in both genotypes (WT: n=5; KO: n=4). (e) Sample traces showing that the KO mice displayed no hyperpolarizing phase at VR, whereas WT animals had a biphasic EPSP–IPSP sequence. The hyperpolarizing IPSPs became apparent in the KO mice when cells were depolarized by DC injection. Conversely, the IPSP was less evident when pyramidal cells from WT mice were hyperpolarized. Error bars represent s.e.m.; **P<0.01.

Mentions: One prediction from these results is that genetic ablation of Ih should similarly hyperpolarize neurons, change the driving force for chloride and prolong the depolarizing phase of the EPSP–IPSP sequence. We examined HCN1 knockout mice and compared them with wild-type littermate controls. Consistent with previous studies2728, HCN1 knockouts lacked the Ih-mediated membrane potential sag following hyperpolarizing step current injection (Fig. 3a). The resting membrane potential of pyramidal cells was more hyperpolarized in the knockout mice (−72.6±2.5 mV) compared with wild-type littermate control animals (−61.9±1.6 mV; P=0.0037; Fig. 3a–c); however, EGABA(A) was similar in both genotypes (Fig. 3b,d). As predicted, the hyperpolarizing phase of the EPSP–IPSP sequence was either absent or reduced in the knockout animals, and the width of the EPSPs was broadened to 193.4±18.4% of the wild-type value (P=0.009; Fig. 3e).


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

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

HCN1 deletion results in the loss of the hyperpolarizing effects of GABAA receptor-mediated inhibition.(a) Example traces showing voltage responses to current steps injections in wild-type (WT) mice and HCN1 knockout (KO) mice. (b) An example plot showing that, unlike WT mice, HCN1 KO mice lacked a hyperpolarizing GABAA receptor-mediated driving force. Data points were fitted with a second-order polynomial function. (c) Comparison of VR in HCN1 KO mice and WT mice (WT: n=5; KO: n=8). (d) Summary plot of EGABA(A) in both genotypes (WT: n=5; KO: n=4). (e) Sample traces showing that the KO mice displayed no hyperpolarizing phase at VR, whereas WT animals had a biphasic EPSP–IPSP sequence. The hyperpolarizing IPSPs became apparent in the KO mice when cells were depolarized by DC injection. Conversely, the IPSP was less evident when pyramidal cells from WT mice were hyperpolarized. Error bars represent s.e.m.; **P<0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: HCN1 deletion results in the loss of the hyperpolarizing effects of GABAA receptor-mediated inhibition.(a) Example traces showing voltage responses to current steps injections in wild-type (WT) mice and HCN1 knockout (KO) mice. (b) An example plot showing that, unlike WT mice, HCN1 KO mice lacked a hyperpolarizing GABAA receptor-mediated driving force. Data points were fitted with a second-order polynomial function. (c) Comparison of VR in HCN1 KO mice and WT mice (WT: n=5; KO: n=8). (d) Summary plot of EGABA(A) in both genotypes (WT: n=5; KO: n=4). (e) Sample traces showing that the KO mice displayed no hyperpolarizing phase at VR, whereas WT animals had a biphasic EPSP–IPSP sequence. The hyperpolarizing IPSPs became apparent in the KO mice when cells were depolarized by DC injection. Conversely, the IPSP was less evident when pyramidal cells from WT mice were hyperpolarized. Error bars represent s.e.m.; **P<0.01.
Mentions: One prediction from these results is that genetic ablation of Ih should similarly hyperpolarize neurons, change the driving force for chloride and prolong the depolarizing phase of the EPSP–IPSP sequence. We examined HCN1 knockout mice and compared them with wild-type littermate controls. Consistent with previous studies2728, HCN1 knockouts lacked the Ih-mediated membrane potential sag following hyperpolarizing step current injection (Fig. 3a). The resting membrane potential of pyramidal cells was more hyperpolarized in the knockout mice (−72.6±2.5 mV) compared with wild-type littermate control animals (−61.9±1.6 mV; P=0.0037; Fig. 3a–c); however, EGABA(A) was similar in both genotypes (Fig. 3b,d). As predicted, the hyperpolarizing phase of the EPSP–IPSP sequence was either absent or reduced in the knockout animals, and the width of the EPSPs was broadened to 193.4±18.4% of the wild-type value (P=0.009; Fig. 3e).

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