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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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Blocking Ih changes the VR–EGABA(A) relationship in CA1 pyramidal cells.(a) In control conditions, all cells had negative EGABA(A) compared with VR (n=12). Sample IPSPs at different membrane potentials from a typical experiment are shown in the inset. Data points were fitted with a second-order polynomial function. (b) Time course of the changes in VR following the application of ZD-7288 (n=12). (c) Effect of ZD-7288 on VR (filled circles are mean values, open circles are data from individual experiments; n=12). (d) Effect of Ih block on EGABA(A) (filled circles are mean values, open circles are data from individual experiments; n=12). (e) Summary graph showing the effect of ZD-7288 on EGABA(A) and VR. EGABA(A) became more depolarized than VR in 10 out of 12 cells (open circles: control, filled circles: in ZD-7288). Error bars represent s.e.m.; *P<0.05, **P<0.01.
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f4: Blocking Ih changes the VR–EGABA(A) relationship in CA1 pyramidal cells.(a) In control conditions, all cells had negative EGABA(A) compared with VR (n=12). Sample IPSPs at different membrane potentials from a typical experiment are shown in the inset. Data points were fitted with a second-order polynomial function. (b) Time course of the changes in VR following the application of ZD-7288 (n=12). (c) Effect of ZD-7288 on VR (filled circles are mean values, open circles are data from individual experiments; n=12). (d) Effect of Ih block on EGABA(A) (filled circles are mean values, open circles are data from individual experiments; n=12). (e) Summary graph showing the effect of ZD-7288 on EGABA(A) and VR. EGABA(A) became more depolarized than VR in 10 out of 12 cells (open circles: control, filled circles: in ZD-7288). Error bars represent s.e.m.; *P<0.05, **P<0.01.

Mentions: The results thus far indicate that Ih-dependent neuronal depolarization is necessary to maintain a hyperpolarizing effect of GABAA receptor currents. We directly tested this hypothesis using gramicidin perforated-patch current-clamp recordings, which minimize perturbation of the internal Cl− concentration. EGABA(A) was determined from the reversal potential of evoked IPSPs, and was uniformly negative to VR (mean EGABA(A)–VR: −5.2±1.0 mV; n=12; P=0.0003; Fig. 4a). In all cells, application of ZD-7288 resulted in a significant negative shift in VR (−8.6±0.9 mV; P=7.4×10−7; n=12; Fig. 4b,c). In contrast, inhibition of Ih led to only a small depolarizing shift in EGABA(A) (2.1±0.8 mV; P=0.03; Fig. 4d). The net effect of blocking Ih was to make VR more negative than EGABA(A) in 10 out of 12 cells (mean EGABA(A)–VR: 5.5±1.3 mV; n=12; P=0.0013; Fig. 4e). This demonstrates a major role of Ih in maintaining a hyperpolarizing driving force for fast GABAergic transmission.


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

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

Blocking Ih changes the VR–EGABA(A) relationship in CA1 pyramidal cells.(a) In control conditions, all cells had negative EGABA(A) compared with VR (n=12). Sample IPSPs at different membrane potentials from a typical experiment are shown in the inset. Data points were fitted with a second-order polynomial function. (b) Time course of the changes in VR following the application of ZD-7288 (n=12). (c) Effect of ZD-7288 on VR (filled circles are mean values, open circles are data from individual experiments; n=12). (d) Effect of Ih block on EGABA(A) (filled circles are mean values, open circles are data from individual experiments; n=12). (e) Summary graph showing the effect of ZD-7288 on EGABA(A) and VR. EGABA(A) became more depolarized than VR in 10 out of 12 cells (open circles: control, filled circles: in ZD-7288). Error bars represent s.e.m.; *P<0.05, **P<0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Blocking Ih changes the VR–EGABA(A) relationship in CA1 pyramidal cells.(a) In control conditions, all cells had negative EGABA(A) compared with VR (n=12). Sample IPSPs at different membrane potentials from a typical experiment are shown in the inset. Data points were fitted with a second-order polynomial function. (b) Time course of the changes in VR following the application of ZD-7288 (n=12). (c) Effect of ZD-7288 on VR (filled circles are mean values, open circles are data from individual experiments; n=12). (d) Effect of Ih block on EGABA(A) (filled circles are mean values, open circles are data from individual experiments; n=12). (e) Summary graph showing the effect of ZD-7288 on EGABA(A) and VR. EGABA(A) became more depolarized than VR in 10 out of 12 cells (open circles: control, filled circles: in ZD-7288). Error bars represent s.e.m.; *P<0.05, **P<0.01.
Mentions: The results thus far indicate that Ih-dependent neuronal depolarization is necessary to maintain a hyperpolarizing effect of GABAA receptor currents. We directly tested this hypothesis using gramicidin perforated-patch current-clamp recordings, which minimize perturbation of the internal Cl− concentration. EGABA(A) was determined from the reversal potential of evoked IPSPs, and was uniformly negative to VR (mean EGABA(A)–VR: −5.2±1.0 mV; n=12; P=0.0003; Fig. 4a). In all cells, application of ZD-7288 resulted in a significant negative shift in VR (−8.6±0.9 mV; P=7.4×10−7; n=12; Fig. 4b,c). In contrast, inhibition of Ih led to only a small depolarizing shift in EGABA(A) (2.1±0.8 mV; P=0.03; Fig. 4d). The net effect of blocking Ih was to make VR more negative than EGABA(A) in 10 out of 12 cells (mean EGABA(A)–VR: 5.5±1.3 mV; n=12; P=0.0013; Fig. 4e). This demonstrates a major role of Ih in maintaining a hyperpolarizing driving force for fast GABAergic transmission.

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