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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 induced a change in synaptic AMPA receptor phenotype. A. Average sEPSCs displayed an inwardly rectifying I–V relationship in control, and became more linear following noradrenaline treatment (control, n = 4; noradrenaline treatment, n = 8). Cerebellar slices were incubated with kynurenic acid (1 mM) and picrotoxin (100 µM) in the absence (control) or presence of noradrenaline (10 µM, 3 h). Following each treatment noradrenaline and kynurenic acid were washed out prior to recordings of sEPSCs. B. The decay time of sEPSCs at −60 mV increased following noradrenaline treatment (Kolmogorov-Smirnov test, P < 0.0001). Cumulative distribution of decay time constant of EPSC at −60 mV of individual synaptic events from 4 control cells and 8 noradrenaline treated cells. C. Noradrenaline also induced a change in the I–V relationship of evoked EPSCs at the parallel fibre to stellate cell synapse (control, n = 4; noradrenaline treatment, n = 5). D. Summary of rectification index of EPSCs. Cerebellar slices were incubated with 10 µM noradrenaline for 3 h, 0.5 h (+2.5 h in picrotoxin and kynurenic acid control, n = 5; picrotoxin and kynurenic acid control, n = 4). E. CNQX (10 µM) and cyclothiazide (100 µM) evoked inward currents of comparable amplitude in control (n = 4) and noradrenaline treated cells (n = 5; two way ANOVA test, P = 0.39). (*, P < 0.05; **, P < 0.005). F. Noradrenaline (10 µM) increased the frequency (left panel) and duration (right panel) of spontaneous action potentials in stellate cells at 36°C (frequency, n = 5, P < 0.05; duration, n = 5, P < 0.005). Error bars show ± s.e.m.
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Figure 3: Noradrenaline induced a change in synaptic AMPA receptor phenotype. A. Average sEPSCs displayed an inwardly rectifying I–V relationship in control, and became more linear following noradrenaline treatment (control, n = 4; noradrenaline treatment, n = 8). Cerebellar slices were incubated with kynurenic acid (1 mM) and picrotoxin (100 µM) in the absence (control) or presence of noradrenaline (10 µM, 3 h). Following each treatment noradrenaline and kynurenic acid were washed out prior to recordings of sEPSCs. B. The decay time of sEPSCs at −60 mV increased following noradrenaline treatment (Kolmogorov-Smirnov test, P < 0.0001). Cumulative distribution of decay time constant of EPSC at −60 mV of individual synaptic events from 4 control cells and 8 noradrenaline treated cells. C. Noradrenaline also induced a change in the I–V relationship of evoked EPSCs at the parallel fibre to stellate cell synapse (control, n = 4; noradrenaline treatment, n = 5). D. Summary of rectification index of EPSCs. Cerebellar slices were incubated with 10 µM noradrenaline for 3 h, 0.5 h (+2.5 h in picrotoxin and kynurenic acid control, n = 5; picrotoxin and kynurenic acid control, n = 4). E. CNQX (10 µM) and cyclothiazide (100 µM) evoked inward currents of comparable amplitude in control (n = 4) and noradrenaline treated cells (n = 5; two way ANOVA test, P = 0.39). (*, P < 0.05; **, P < 0.005). F. Noradrenaline (10 µM) increased the frequency (left panel) and duration (right panel) of spontaneous action potentials in stellate cells at 36°C (frequency, n = 5, P < 0.05; duration, n = 5, P < 0.005). Error bars show ± s.e.m.

Mentions: We next examined whether application of noradrenaline directly to brain slices can mimic the fear-induced switch in AMPAR phenotype at stellate cell synapses. Application of noradrenaline (10 µM) via the bath perfusate (at 36°C) produced a modest increase in sEPSC frequency (control, 0.37± 0.16; noradrenaline, 0.58 ± 0.34 Hz; n = 6; P = 0.24). To avoid a contribution of altered glutamate or GABA release, we incubated slices in the presence of kynurenic acid (1 mM, to block AMPARs and NMDARs) and picrotoxin (100 µM, to block GABAARs; Fig. S1). Kynurenic acid and picrotoxin (3h) did not detectably alter the sEPSC rectification index (0.25 ± 0.07, n = 4; P = 0.23 vs. no treatment). Application of noradrenaline (3 h) in the presence of kynurenic acid and picrotoxin caused a switch in the I–V relation of the sEPSC (Fig. 3A) and evoked EPSC (Fig. 3C) from inwardly rectifying to near linear. Whereas noradrenaline increased the sEPSC amplitude from 7.8 ±1.7 (control) to 16.3 ±1.1 pA at +40 mV (n = 8, P < 0.001), it produced little or no change in EPSC amplitude at −60 mV (control, −46.9 ± 6.7, n = 4; noradrenaline, −39.0 ±1.6 pA; n = 8). Noradrenaline increased the rectification index from inwardly rectifying (control, 0.25 ± 0.07) to nearly linear (noradrenaline, 0.74 ± 0.10; P< 0.01; Fig. 3D). Noradrenaline also prolonged the decay time constant of sEPSCs at −60 mV (control, 0.95 ± 0.04; noradrenaline, 1.29 ± 0.09 ms; P < 0.02; (Fig. 3B). Together, these results strongly suggest that noradrenaline promotes synaptic incorporation of GluR2-containing receptors. Noradrenaline treatment for 0.5 h, followed by 2.5 h incubation, increased the rectification index of sEPSCs (0.57 ± 0.12; n = 5; P < 0.05; Fig. 3D). These findings indicate that noradrenaline treatment for 0.5 h) is sufficient to induce the switch in synaptic AMPAR phenotype in stellate cells, although the switch is delayed relative to its induction.


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 induced a change in synaptic AMPA receptor phenotype. A. Average sEPSCs displayed an inwardly rectifying I–V relationship in control, and became more linear following noradrenaline treatment (control, n = 4; noradrenaline treatment, n = 8). Cerebellar slices were incubated with kynurenic acid (1 mM) and picrotoxin (100 µM) in the absence (control) or presence of noradrenaline (10 µM, 3 h). Following each treatment noradrenaline and kynurenic acid were washed out prior to recordings of sEPSCs. B. The decay time of sEPSCs at −60 mV increased following noradrenaline treatment (Kolmogorov-Smirnov test, P < 0.0001). Cumulative distribution of decay time constant of EPSC at −60 mV of individual synaptic events from 4 control cells and 8 noradrenaline treated cells. C. Noradrenaline also induced a change in the I–V relationship of evoked EPSCs at the parallel fibre to stellate cell synapse (control, n = 4; noradrenaline treatment, n = 5). D. Summary of rectification index of EPSCs. Cerebellar slices were incubated with 10 µM noradrenaline for 3 h, 0.5 h (+2.5 h in picrotoxin and kynurenic acid control, n = 5; picrotoxin and kynurenic acid control, n = 4). E. CNQX (10 µM) and cyclothiazide (100 µM) evoked inward currents of comparable amplitude in control (n = 4) and noradrenaline treated cells (n = 5; two way ANOVA test, P = 0.39). (*, P < 0.05; **, P < 0.005). F. Noradrenaline (10 µM) increased the frequency (left panel) and duration (right panel) of spontaneous action potentials in stellate cells at 36°C (frequency, n = 5, P < 0.05; duration, n = 5, P < 0.005). Error bars show ± s.e.m.
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Figure 3: Noradrenaline induced a change in synaptic AMPA receptor phenotype. A. Average sEPSCs displayed an inwardly rectifying I–V relationship in control, and became more linear following noradrenaline treatment (control, n = 4; noradrenaline treatment, n = 8). Cerebellar slices were incubated with kynurenic acid (1 mM) and picrotoxin (100 µM) in the absence (control) or presence of noradrenaline (10 µM, 3 h). Following each treatment noradrenaline and kynurenic acid were washed out prior to recordings of sEPSCs. B. The decay time of sEPSCs at −60 mV increased following noradrenaline treatment (Kolmogorov-Smirnov test, P < 0.0001). Cumulative distribution of decay time constant of EPSC at −60 mV of individual synaptic events from 4 control cells and 8 noradrenaline treated cells. C. Noradrenaline also induced a change in the I–V relationship of evoked EPSCs at the parallel fibre to stellate cell synapse (control, n = 4; noradrenaline treatment, n = 5). D. Summary of rectification index of EPSCs. Cerebellar slices were incubated with 10 µM noradrenaline for 3 h, 0.5 h (+2.5 h in picrotoxin and kynurenic acid control, n = 5; picrotoxin and kynurenic acid control, n = 4). E. CNQX (10 µM) and cyclothiazide (100 µM) evoked inward currents of comparable amplitude in control (n = 4) and noradrenaline treated cells (n = 5; two way ANOVA test, P = 0.39). (*, P < 0.05; **, P < 0.005). F. Noradrenaline (10 µM) increased the frequency (left panel) and duration (right panel) of spontaneous action potentials in stellate cells at 36°C (frequency, n = 5, P < 0.05; duration, n = 5, P < 0.005). Error bars show ± s.e.m.
Mentions: We next examined whether application of noradrenaline directly to brain slices can mimic the fear-induced switch in AMPAR phenotype at stellate cell synapses. Application of noradrenaline (10 µM) via the bath perfusate (at 36°C) produced a modest increase in sEPSC frequency (control, 0.37± 0.16; noradrenaline, 0.58 ± 0.34 Hz; n = 6; P = 0.24). To avoid a contribution of altered glutamate or GABA release, we incubated slices in the presence of kynurenic acid (1 mM, to block AMPARs and NMDARs) and picrotoxin (100 µM, to block GABAARs; Fig. S1). Kynurenic acid and picrotoxin (3h) did not detectably alter the sEPSC rectification index (0.25 ± 0.07, n = 4; P = 0.23 vs. no treatment). Application of noradrenaline (3 h) in the presence of kynurenic acid and picrotoxin caused a switch in the I–V relation of the sEPSC (Fig. 3A) and evoked EPSC (Fig. 3C) from inwardly rectifying to near linear. Whereas noradrenaline increased the sEPSC amplitude from 7.8 ±1.7 (control) to 16.3 ±1.1 pA at +40 mV (n = 8, P < 0.001), it produced little or no change in EPSC amplitude at −60 mV (control, −46.9 ± 6.7, n = 4; noradrenaline, −39.0 ±1.6 pA; n = 8). Noradrenaline increased the rectification index from inwardly rectifying (control, 0.25 ± 0.07) to nearly linear (noradrenaline, 0.74 ± 0.10; P< 0.01; Fig. 3D). Noradrenaline also prolonged the decay time constant of sEPSCs at −60 mV (control, 0.95 ± 0.04; noradrenaline, 1.29 ± 0.09 ms; P < 0.02; (Fig. 3B). Together, these results strongly suggest that noradrenaline promotes synaptic incorporation of GluR2-containing receptors. Noradrenaline treatment for 0.5 h, followed by 2.5 h incubation, increased the rectification index of sEPSCs (0.57 ± 0.12; n = 5; P < 0.05; Fig. 3D). These findings indicate that noradrenaline treatment for 0.5 h) is sufficient to induce the switch in synaptic AMPAR phenotype in stellate cells, although the switch is delayed relative to its induction.

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