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Biphasic somatic A-type K channel downregulation mediates intrinsic plasticity in hippocampal CA1 pyramidal neurons.

Jung SC, Hoffman DA - PLoS ONE (2009)

Bottom Line: Induction of LTP resulted in an immediate but short lasting hyperpolarization of the voltage-dependence of steady-state A-type K(+) channel inactivation along with a progressive, long-lasting decrease in peak A-current density.Blocking clathrin-mediated endocytosis prevented the A-current decrease and most measures of intrinsic plasticity.Finally we show that intrinsic plasticity resulted in a global enhancement of EPSP-spike coupling.

View Article: PubMed Central - PubMed

Affiliation: Molecular Neurophysiology and Biophysics Unit, Laboratory of Cellular and Synaptic Neurophysiology, NICHD, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
Since its original description, the induction of synaptic long-term potentiation (LTP) has been known to be accompanied by a lasting increase in the intrinsic excitability (intrinsic plasticity) of hippocampal neurons. Recent evidence shows that dendritic excitability can be enhanced by an activity-dependent decrease in the activity of A-type K(+) channels. In the present manuscript, we examined the role of A-type K(+) channels in regulating intrinsic excitability of CA1 pyramidal neurons of the hippocampus after synapse-specific LTP induction. In electrophysiological recordings we found that LTP induced a potentiation of excitability which was accompanied by a two-phased change in A-type K(+) channel activity recorded in nucleated patches from organotypic slices of rat hippocampus. Induction of LTP resulted in an immediate but short lasting hyperpolarization of the voltage-dependence of steady-state A-type K(+) channel inactivation along with a progressive, long-lasting decrease in peak A-current density. Blocking clathrin-mediated endocytosis prevented the A-current decrease and most measures of intrinsic plasticity. These results suggest that two temporally distinct but overlapping mechanisms of A-channel downregulation together contribute to the plasticity of intrinsic excitability. Finally we show that intrinsic plasticity resulted in a global enhancement of EPSP-spike coupling.

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Synaptic potentiation increases intrinsic excitability.A. Experimental schema for conditioning stimulation to induce synaptic potentiation. Synaptic LTP was induced by 2 Hz stimulation of the Schaffer collateral (S.C.) pathway for 1 min paired with depolarization to a 0 mV holding potential (“Paired”). For control, the same stimulating protocol was delivered without depolarization (“Unpaired”). The right panel shows synaptic responses of individual neurons before and after conditioning stimulation. Synaptic potentiation was measured as the amplitude of EPSCs triggered by S.C. test stimulation (0.1 Hz) before and after conditioning stimulation. Inset traces are EPSCs recorded at the indicated time. Scale bars: 50 pA, 20 ms. To measure intrinsic excitability, a series of current injections (+50 to +200 pA in 50 pA increments) was delivered to elicit APs (“I-Vs”, arrows) in I-clamp mode every 10 min before and after LTP. B. Pooled LTP data from “paired” and “unpaired” neurons. After a 5 min stable baseline, significant potentiation of synaptic strength was observed in neurons receiving paired stimulation while unpaired neurons showed no change in EPSC amplitude. Error bars represent SEM. C. Examples of AP firing patterns triggered by current injections before and 30 min after conditioning stimulation. Current injections over 100 pA generally fired APs. Firing rates increased after conditioning stimulation in paired but not in unpaired neurons. Scale bars: 20 mV, 200 ms. D. Firing rate was calculated by measuring the interval between first and second AP. Firing rates were significantly increased for all current injections in neurons that received paired stimulation. No change in initial AP frequency was observed in neurons received unpaired stimulation. Error bars represent SEM.
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pone-0006549-g001: Synaptic potentiation increases intrinsic excitability.A. Experimental schema for conditioning stimulation to induce synaptic potentiation. Synaptic LTP was induced by 2 Hz stimulation of the Schaffer collateral (S.C.) pathway for 1 min paired with depolarization to a 0 mV holding potential (“Paired”). For control, the same stimulating protocol was delivered without depolarization (“Unpaired”). The right panel shows synaptic responses of individual neurons before and after conditioning stimulation. Synaptic potentiation was measured as the amplitude of EPSCs triggered by S.C. test stimulation (0.1 Hz) before and after conditioning stimulation. Inset traces are EPSCs recorded at the indicated time. Scale bars: 50 pA, 20 ms. To measure intrinsic excitability, a series of current injections (+50 to +200 pA in 50 pA increments) was delivered to elicit APs (“I-Vs”, arrows) in I-clamp mode every 10 min before and after LTP. B. Pooled LTP data from “paired” and “unpaired” neurons. After a 5 min stable baseline, significant potentiation of synaptic strength was observed in neurons receiving paired stimulation while unpaired neurons showed no change in EPSC amplitude. Error bars represent SEM. C. Examples of AP firing patterns triggered by current injections before and 30 min after conditioning stimulation. Current injections over 100 pA generally fired APs. Firing rates increased after conditioning stimulation in paired but not in unpaired neurons. Scale bars: 20 mV, 200 ms. D. Firing rate was calculated by measuring the interval between first and second AP. Firing rates were significantly increased for all current injections in neurons that received paired stimulation. No change in initial AP frequency was observed in neurons received unpaired stimulation. Error bars represent SEM.

Mentions: Having recently described the activity-dependent trafficking of the A-type K+ channel subunit Kv4.2 in hippocampal neurons [12], we hypothesized that A-channel internalization contributes to intrinsic excitability changes observed in CA1 hippocampal pyramidal neurons after synaptic LTP induction [1], [19]. LTP was induced by pairing low frequency stimulation (2 Hz, 0.1 ms duration, 1 min) of the Schaffer-Collateral pathway with depolarization to 0 mV. We and others have previously found LTP induced in these experimental conditions to be NMDAR- and CaMKII- dependent [20], [21]. We monitored LTP expression by measuring EPSC amplitude change in voltage-clamp mode at −60 mV (Figure 1A and B, “Paired”, 64.33±12.13% increase in EPSC amplitude 40 min after pairing, n = 8, p = 0.007 compared with “Unpaired”). The same conditioning stimulation protocol without depolarization (−60 mV holding potential) did not result in synaptic LTP (Figure 1A–B, “Unpaired”, n = 6, −11.95±9.51% potentiation, 40 min after pairing, p = 0.315). We measured changes in intrinsic excitability by monitoring AP firing patterns induced by a series of step and ramp current injections in whole-cell current clamp recordings (Figure 1 and 2). This firing profile was observed before and every ten minutes after LTP induction. In both groups (Paired and Unpaired), current injections greater than 100 pA were generally required to initiate APs before LTP induction. In some cases APs were observed with 50 pA current injections (paired n = 4, unpaired n = 3). After LTP pairing stimulation, the number of cells firing with 50 pA current injections increased (10 min post-LTP, paired = 6, unpaired = 4). We measured AP firing rate (Hz) between the first and second AP (first interspike interval). Increased firing frequency was observed 10 min after LTP induction and maintained throughout the recordings (Figure 1C and D, “Paired”, +100 pA injection: pre = 38.84±4.27 Hz, 40 min = 54.30±4.79 Hz, p = 0.013) in paired neurons. However, the increased firing rate was not observed in unpaired recordings (Figure 1C and D, “Unpaired”, +100 pA injection: pre = 35.62±4.23 Hz, 40 min = 40.25±6.57 Hz, p = 0.407). These data establish that intrinsic plasticity is observed in CA1 neurons of organotypic slice cultures after depolarization-pairing induced LTP.


Biphasic somatic A-type K channel downregulation mediates intrinsic plasticity in hippocampal CA1 pyramidal neurons.

Jung SC, Hoffman DA - PLoS ONE (2009)

Synaptic potentiation increases intrinsic excitability.A. Experimental schema for conditioning stimulation to induce synaptic potentiation. Synaptic LTP was induced by 2 Hz stimulation of the Schaffer collateral (S.C.) pathway for 1 min paired with depolarization to a 0 mV holding potential (“Paired”). For control, the same stimulating protocol was delivered without depolarization (“Unpaired”). The right panel shows synaptic responses of individual neurons before and after conditioning stimulation. Synaptic potentiation was measured as the amplitude of EPSCs triggered by S.C. test stimulation (0.1 Hz) before and after conditioning stimulation. Inset traces are EPSCs recorded at the indicated time. Scale bars: 50 pA, 20 ms. To measure intrinsic excitability, a series of current injections (+50 to +200 pA in 50 pA increments) was delivered to elicit APs (“I-Vs”, arrows) in I-clamp mode every 10 min before and after LTP. B. Pooled LTP data from “paired” and “unpaired” neurons. After a 5 min stable baseline, significant potentiation of synaptic strength was observed in neurons receiving paired stimulation while unpaired neurons showed no change in EPSC amplitude. Error bars represent SEM. C. Examples of AP firing patterns triggered by current injections before and 30 min after conditioning stimulation. Current injections over 100 pA generally fired APs. Firing rates increased after conditioning stimulation in paired but not in unpaired neurons. Scale bars: 20 mV, 200 ms. D. Firing rate was calculated by measuring the interval between first and second AP. Firing rates were significantly increased for all current injections in neurons that received paired stimulation. No change in initial AP frequency was observed in neurons received unpaired stimulation. Error bars represent SEM.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2717216&req=5

pone-0006549-g001: Synaptic potentiation increases intrinsic excitability.A. Experimental schema for conditioning stimulation to induce synaptic potentiation. Synaptic LTP was induced by 2 Hz stimulation of the Schaffer collateral (S.C.) pathway for 1 min paired with depolarization to a 0 mV holding potential (“Paired”). For control, the same stimulating protocol was delivered without depolarization (“Unpaired”). The right panel shows synaptic responses of individual neurons before and after conditioning stimulation. Synaptic potentiation was measured as the amplitude of EPSCs triggered by S.C. test stimulation (0.1 Hz) before and after conditioning stimulation. Inset traces are EPSCs recorded at the indicated time. Scale bars: 50 pA, 20 ms. To measure intrinsic excitability, a series of current injections (+50 to +200 pA in 50 pA increments) was delivered to elicit APs (“I-Vs”, arrows) in I-clamp mode every 10 min before and after LTP. B. Pooled LTP data from “paired” and “unpaired” neurons. After a 5 min stable baseline, significant potentiation of synaptic strength was observed in neurons receiving paired stimulation while unpaired neurons showed no change in EPSC amplitude. Error bars represent SEM. C. Examples of AP firing patterns triggered by current injections before and 30 min after conditioning stimulation. Current injections over 100 pA generally fired APs. Firing rates increased after conditioning stimulation in paired but not in unpaired neurons. Scale bars: 20 mV, 200 ms. D. Firing rate was calculated by measuring the interval between first and second AP. Firing rates were significantly increased for all current injections in neurons that received paired stimulation. No change in initial AP frequency was observed in neurons received unpaired stimulation. Error bars represent SEM.
Mentions: Having recently described the activity-dependent trafficking of the A-type K+ channel subunit Kv4.2 in hippocampal neurons [12], we hypothesized that A-channel internalization contributes to intrinsic excitability changes observed in CA1 hippocampal pyramidal neurons after synaptic LTP induction [1], [19]. LTP was induced by pairing low frequency stimulation (2 Hz, 0.1 ms duration, 1 min) of the Schaffer-Collateral pathway with depolarization to 0 mV. We and others have previously found LTP induced in these experimental conditions to be NMDAR- and CaMKII- dependent [20], [21]. We monitored LTP expression by measuring EPSC amplitude change in voltage-clamp mode at −60 mV (Figure 1A and B, “Paired”, 64.33±12.13% increase in EPSC amplitude 40 min after pairing, n = 8, p = 0.007 compared with “Unpaired”). The same conditioning stimulation protocol without depolarization (−60 mV holding potential) did not result in synaptic LTP (Figure 1A–B, “Unpaired”, n = 6, −11.95±9.51% potentiation, 40 min after pairing, p = 0.315). We measured changes in intrinsic excitability by monitoring AP firing patterns induced by a series of step and ramp current injections in whole-cell current clamp recordings (Figure 1 and 2). This firing profile was observed before and every ten minutes after LTP induction. In both groups (Paired and Unpaired), current injections greater than 100 pA were generally required to initiate APs before LTP induction. In some cases APs were observed with 50 pA current injections (paired n = 4, unpaired n = 3). After LTP pairing stimulation, the number of cells firing with 50 pA current injections increased (10 min post-LTP, paired = 6, unpaired = 4). We measured AP firing rate (Hz) between the first and second AP (first interspike interval). Increased firing frequency was observed 10 min after LTP induction and maintained throughout the recordings (Figure 1C and D, “Paired”, +100 pA injection: pre = 38.84±4.27 Hz, 40 min = 54.30±4.79 Hz, p = 0.013) in paired neurons. However, the increased firing rate was not observed in unpaired recordings (Figure 1C and D, “Unpaired”, +100 pA injection: pre = 35.62±4.23 Hz, 40 min = 40.25±6.57 Hz, p = 0.407). These data establish that intrinsic plasticity is observed in CA1 neurons of organotypic slice cultures after depolarization-pairing induced LTP.

Bottom Line: Induction of LTP resulted in an immediate but short lasting hyperpolarization of the voltage-dependence of steady-state A-type K(+) channel inactivation along with a progressive, long-lasting decrease in peak A-current density.Blocking clathrin-mediated endocytosis prevented the A-current decrease and most measures of intrinsic plasticity.Finally we show that intrinsic plasticity resulted in a global enhancement of EPSP-spike coupling.

View Article: PubMed Central - PubMed

Affiliation: Molecular Neurophysiology and Biophysics Unit, Laboratory of Cellular and Synaptic Neurophysiology, NICHD, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
Since its original description, the induction of synaptic long-term potentiation (LTP) has been known to be accompanied by a lasting increase in the intrinsic excitability (intrinsic plasticity) of hippocampal neurons. Recent evidence shows that dendritic excitability can be enhanced by an activity-dependent decrease in the activity of A-type K(+) channels. In the present manuscript, we examined the role of A-type K(+) channels in regulating intrinsic excitability of CA1 pyramidal neurons of the hippocampus after synapse-specific LTP induction. In electrophysiological recordings we found that LTP induced a potentiation of excitability which was accompanied by a two-phased change in A-type K(+) channel activity recorded in nucleated patches from organotypic slices of rat hippocampus. Induction of LTP resulted in an immediate but short lasting hyperpolarization of the voltage-dependence of steady-state A-type K(+) channel inactivation along with a progressive, long-lasting decrease in peak A-current density. Blocking clathrin-mediated endocytosis prevented the A-current decrease and most measures of intrinsic plasticity. These results suggest that two temporally distinct but overlapping mechanisms of A-channel downregulation together contribute to the plasticity of intrinsic excitability. Finally we show that intrinsic plasticity resulted in a global enhancement of EPSP-spike coupling.

Show MeSH
Related in: MedlinePlus