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A single fear-inducing stimulus induces a transcription-dependent switch in synaptic AMPAR phenotype.

Liu Y, Formisano L, Savtchouk I, Takayasu Y, Szabó G, Zukin RS, Liu SJ - Nat. Neurosci. (2009)

Bottom Line: The subsequent rise in intracellular Ca(2+) and activation of Ca(2+)-sensitive ERK/MAPK signaling triggered new GluR2 gene transcription and a switch in the synaptic AMPAR phenotype from GluR2-lacking, Ca(2+)-permeable receptors to GluR2-containing, Ca(2+)-impermeable receptors on the order of hours.The change in glutamate receptor phenotype altered synaptic efficacy in cerebellar stellate cells.Thus, a single fear-inducing stimulus can induce a long-term change in synaptic receptor phenotype and may alter the activity of an inhibitory neural network.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Pennsylvania State University, University Park, Pennsylvania, USA.

ABSTRACT
Changes in emotional state are known to alter neuronal excitability and can modify learning and memory formation. Such experience-dependent neuronal plasticity can be long-lasting and is thought to involve the regulation of gene transcription. We found that a single fear-inducing stimulus increased GluR2 (also known as Gria2) mRNA abundance and promoted synaptic incorporation of GluR2-containing AMPA receptors (AMPARs) in mouse cerebellar stellate cells. The switch in synaptic AMPAR phenotype was mediated by noradrenaline and action potential prolongation. The subsequent rise in intracellular Ca(2+) and activation of Ca(2+)-sensitive ERK/MAPK signaling triggered new GluR2 gene transcription and a switch in the synaptic AMPAR phenotype from GluR2-lacking, Ca(2+)-permeable receptors to GluR2-containing, Ca(2+)-impermeable receptors on the order of hours. The change in glutamate receptor phenotype altered synaptic efficacy in cerebellar stellate cells. Thus, a single fear-inducing stimulus can induce a long-term change in synaptic receptor phenotype and may alter the activity of an inhibitory neural network.

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Noradrenaline increases Ca influx during the action potential and Ca entry via L-type Ca channels is required for NA-induced change in AMPAR phenotype. A. Duration of Ca2+ currents was enhanced using NA-AP as the voltage command, compared to control (n = 5). Nifedipine (20 µM) blocked most of the Ca2+ current using control-AP and NA-AP as the voltage command (n = 5). B. Following 3 hour incubation with noradrenaline and nifedipine sEPSCs displayed an inwardly rectifying I–V relationship (n = 6). C. Summary of rectification index of EPSCs (nifedipine alone, n = 5). (*, P < 0.05; **, P < 0.005). Error bars show ± s.e.m.
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Figure 5: Noradrenaline increases Ca influx during the action potential and Ca entry via L-type Ca channels is required for NA-induced change in AMPAR phenotype. A. Duration of Ca2+ currents was enhanced using NA-AP as the voltage command, compared to control (n = 5). Nifedipine (20 µM) blocked most of the Ca2+ current using control-AP and NA-AP as the voltage command (n = 5). B. Following 3 hour incubation with noradrenaline and nifedipine sEPSCs displayed an inwardly rectifying I–V relationship (n = 6). C. Summary of rectification index of EPSCs (nifedipine alone, n = 5). (*, P < 0.05; **, P < 0.005). Error bars show ± s.e.m.

Mentions: Spike broadening could increase Ca2+ entry via voltage-gated Ca2+ channels during action potentials. To examine whether the noradrenaline-induced increase in action potential duration is associated with enhanced Ca2+ entry, we measured Ca2+ currents in stellate cells under voltage-clamp using action potential waveforms that mimicked either action potential in control (control-AP) or in the presence of noradrenaline (NA-AP). Ca2+ entry during a NA-AP (defined as current integrated over action potential duration) was ~40% greater than that of a control-AP waveform (n = 5; control-AP: 176 ± 32; NA-AP: 229 ± 34 pA.ms; P < 0.05; Fig. 5A). The L-type Cav1 blocker, nifedipine (20 µM), blocked 62.0 ± 4.6% (n = 5) of the Ca2+ current during a control-AP waveform (Fig. 5A), indicating that a substantial fraction of the Ca2+ current associated with an action potential is mediated by L-type channels. Application of nifedipine alone increased the rectification index of the EPSC (nifedipine, 0.49 ± 0.06; n = 5; P < 0.05 vs. control; Fig. 5C) to an extent less than that produced by noradrenaline (noradrenaline, 0.89 ± 0.05, n = 8; P < 0.05 nifedipine vs. noradrenaline). However, nifedipine blocked the noradrenaline-induced switch in AMPAR phenotype, assessed by the sEPSC amplitude at +40 mV (noradrenaline+nifedipine, 11.3 ± 0.6 pA; n = 6; P < 0.005 vs. noradrenaline) and rectification index (noradrenaline+nifedipine, 0.35 ± 0.03; P < 0.005 vs. noradrenaline; P < 0.05 vs. nifedipine alone; Fig. 5B, C). These findings are consistent with nifedipine-induced block rather than occlusion of the noradrenaline effect and indicate that Ca2+ entry via L-type Ca2+ channels is required for the noradrenaline-induced switch in AMPAR phenotype at stellate cell synapses.


A single fear-inducing stimulus induces a transcription-dependent switch in synaptic AMPAR phenotype.

Liu Y, Formisano L, Savtchouk I, Takayasu Y, Szabó G, Zukin RS, Liu SJ - Nat. Neurosci. (2009)

Noradrenaline increases Ca influx during the action potential and Ca entry via L-type Ca channels is required for NA-induced change in AMPAR phenotype. A. Duration of Ca2+ currents was enhanced using NA-AP as the voltage command, compared to control (n = 5). Nifedipine (20 µM) blocked most of the Ca2+ current using control-AP and NA-AP as the voltage command (n = 5). B. Following 3 hour incubation with noradrenaline and nifedipine sEPSCs displayed an inwardly rectifying I–V relationship (n = 6). C. Summary of rectification index of EPSCs (nifedipine alone, n = 5). (*, P < 0.05; **, P < 0.005). Error bars show ± s.e.m.
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Figure 5: Noradrenaline increases Ca influx during the action potential and Ca entry via L-type Ca channels is required for NA-induced change in AMPAR phenotype. A. Duration of Ca2+ currents was enhanced using NA-AP as the voltage command, compared to control (n = 5). Nifedipine (20 µM) blocked most of the Ca2+ current using control-AP and NA-AP as the voltage command (n = 5). B. Following 3 hour incubation with noradrenaline and nifedipine sEPSCs displayed an inwardly rectifying I–V relationship (n = 6). C. Summary of rectification index of EPSCs (nifedipine alone, n = 5). (*, P < 0.05; **, P < 0.005). Error bars show ± s.e.m.
Mentions: Spike broadening could increase Ca2+ entry via voltage-gated Ca2+ channels during action potentials. To examine whether the noradrenaline-induced increase in action potential duration is associated with enhanced Ca2+ entry, we measured Ca2+ currents in stellate cells under voltage-clamp using action potential waveforms that mimicked either action potential in control (control-AP) or in the presence of noradrenaline (NA-AP). Ca2+ entry during a NA-AP (defined as current integrated over action potential duration) was ~40% greater than that of a control-AP waveform (n = 5; control-AP: 176 ± 32; NA-AP: 229 ± 34 pA.ms; P < 0.05; Fig. 5A). The L-type Cav1 blocker, nifedipine (20 µM), blocked 62.0 ± 4.6% (n = 5) of the Ca2+ current during a control-AP waveform (Fig. 5A), indicating that a substantial fraction of the Ca2+ current associated with an action potential is mediated by L-type channels. Application of nifedipine alone increased the rectification index of the EPSC (nifedipine, 0.49 ± 0.06; n = 5; P < 0.05 vs. control; Fig. 5C) to an extent less than that produced by noradrenaline (noradrenaline, 0.89 ± 0.05, n = 8; P < 0.05 nifedipine vs. noradrenaline). However, nifedipine blocked the noradrenaline-induced switch in AMPAR phenotype, assessed by the sEPSC amplitude at +40 mV (noradrenaline+nifedipine, 11.3 ± 0.6 pA; n = 6; P < 0.005 vs. noradrenaline) and rectification index (noradrenaline+nifedipine, 0.35 ± 0.03; P < 0.005 vs. noradrenaline; P < 0.05 vs. nifedipine alone; Fig. 5B, C). These findings are consistent with nifedipine-induced block rather than occlusion of the noradrenaline effect and indicate that Ca2+ entry via L-type Ca2+ channels is required for the noradrenaline-induced switch in AMPAR phenotype at stellate cell synapses.

Bottom Line: The subsequent rise in intracellular Ca(2+) and activation of Ca(2+)-sensitive ERK/MAPK signaling triggered new GluR2 gene transcription and a switch in the synaptic AMPAR phenotype from GluR2-lacking, Ca(2+)-permeable receptors to GluR2-containing, Ca(2+)-impermeable receptors on the order of hours.The change in glutamate receptor phenotype altered synaptic efficacy in cerebellar stellate cells.Thus, a single fear-inducing stimulus can induce a long-term change in synaptic receptor phenotype and may alter the activity of an inhibitory neural network.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Pennsylvania State University, University Park, Pennsylvania, USA.

ABSTRACT
Changes in emotional state are known to alter neuronal excitability and can modify learning and memory formation. Such experience-dependent neuronal plasticity can be long-lasting and is thought to involve the regulation of gene transcription. We found that a single fear-inducing stimulus increased GluR2 (also known as Gria2) mRNA abundance and promoted synaptic incorporation of GluR2-containing AMPA receptors (AMPARs) in mouse cerebellar stellate cells. The switch in synaptic AMPAR phenotype was mediated by noradrenaline and action potential prolongation. The subsequent rise in intracellular Ca(2+) and activation of Ca(2+)-sensitive ERK/MAPK signaling triggered new GluR2 gene transcription and a switch in the synaptic AMPAR phenotype from GluR2-lacking, Ca(2+)-permeable receptors to GluR2-containing, Ca(2+)-impermeable receptors on the order of hours. The change in glutamate receptor phenotype altered synaptic efficacy in cerebellar stellate cells. Thus, a single fear-inducing stimulus can induce a long-term change in synaptic receptor phenotype and may alter the activity of an inhibitory neural network.

Show MeSH
Related in: MedlinePlus