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The NO-cGMP-PKG signaling pathway coordinately regulates ERK and ERK-driven gene expression at pre- and postsynaptic sites following LTP-inducing stimulation of thalamo-amygdala synapses.

Ping J, Schafe GE - Neural Plast. (2011)

Bottom Line: Here, we show that LTP-inducing stimulation of thalamo-LA inputs regulates the activation of ERK and the expression of ERK-driven immediate early genes (IEGs) in both the LA and MGm/PIN.Further, we show that pharmacological blockade of NMDAR-driven synaptic plasticity, NOS activation, or PKG signaling in the LA significantly impairs high-frequency stimulation-(HFS-) induced ERK activation and IEG expression in both regions, while blockade of extracellular NO signaling in the LA impairs HFS-induced ERK activation and IEG expression exclusively in the MGm/PIN.These findings suggest that NMDAR-driven synaptic plasticity and NO-cGMP-PKG signaling within the LA coordinately regulate ERK-driven gene expression in both the LA and the MGm/PIN following LTP induction at thalamo-LA synapses, and that synaptic plasticity in the LA promotes ERK-driven transcription in MGm/PIN neurons via NO-driven "retrograde signaling".

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, Yale University, New Haven, CT 06520, USA.

ABSTRACT
Long-term potentiation (LTP) at thalamic input synapses to the lateral nucleus of the amygdala (LA) has been proposed as a cellular mechanism of the formation of auditory fear memories. We have previously shown that signaling via ERK/MAPK in both the LA and the medial division of the medial geniculate nucleus/posterior intralaminar nucleus (MGm/PIN) is critical for LTP at thalamo-LA synapses. Here, we show that LTP-inducing stimulation of thalamo-LA inputs regulates the activation of ERK and the expression of ERK-driven immediate early genes (IEGs) in both the LA and MGm/PIN. Further, we show that pharmacological blockade of NMDAR-driven synaptic plasticity, NOS activation, or PKG signaling in the LA significantly impairs high-frequency stimulation-(HFS-) induced ERK activation and IEG expression in both regions, while blockade of extracellular NO signaling in the LA impairs HFS-induced ERK activation and IEG expression exclusively in the MGm/PIN. These findings suggest that NMDAR-driven synaptic plasticity and NO-cGMP-PKG signaling within the LA coordinately regulate ERK-driven gene expression in both the LA and the MGm/PIN following LTP induction at thalamo-LA synapses, and that synaptic plasticity in the LA promotes ERK-driven transcription in MGm/PIN neurons via NO-driven "retrograde signaling".

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High-frequency stimulation of the MGm/PIN promotes ERK-driven IEG expression in both the LA and MGm/PIN. (a) Placement of stimulation electrode and schematic of the experimental protocol. Rats were given HFS or LFS and sacrificed 2 hours after stimulation. (b) Images of Western blots for Arc/Arg3.1, c-Fos, EGR-1, and GAPDH from both LA (top) and MGm/PIN samples (bottom). (c) Mean (±SEM) percent IEG immunoreactivity from LA punches taken from rats given HFS (n = 9) or LFS (n = 9). (d) Mean (±SEM) percent IEG immunoreactivity from MGm/PIN punches taken from rats given HFS (n = 9) or LFS (n = 9). In each figure, IEG levels have been normalized to GAPDH for each sample, and IEG expression on the ipsilateral side has been expressed as a percentage of that on the contralateral side for each rat. *P < .05 relative to the ipsilateral side N.S. = not significant.
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fig2: High-frequency stimulation of the MGm/PIN promotes ERK-driven IEG expression in both the LA and MGm/PIN. (a) Placement of stimulation electrode and schematic of the experimental protocol. Rats were given HFS or LFS and sacrificed 2 hours after stimulation. (b) Images of Western blots for Arc/Arg3.1, c-Fos, EGR-1, and GAPDH from both LA (top) and MGm/PIN samples (bottom). (c) Mean (±SEM) percent IEG immunoreactivity from LA punches taken from rats given HFS (n = 9) or LFS (n = 9). (d) Mean (±SEM) percent IEG immunoreactivity from MGm/PIN punches taken from rats given HFS (n = 9) or LFS (n = 9). In each figure, IEG levels have been normalized to GAPDH for each sample, and IEG expression on the ipsilateral side has been expressed as a percentage of that on the contralateral side for each rat. *P < .05 relative to the ipsilateral side N.S. = not significant.

Mentions: In our first series of experiments, we observed significant increases in ERK activation in the LA and MGm/PIN following HFS of the thalamo-LA pathway. In the present experiments, we used a combination of Western blotting and immunohistochemistry to examine whether LTP-inducing stimulation of thalamic input synapses to the LA regulate the ERK-driven IEGs Arc/Arg3.1, EGR-1 and c-Fos in the LA and the MGm/PIN. As before, anesthetized rats received either HFS or LFS of thalamic inputs to the LA and were sacrificed by decapitation 2 hours later (Figures 2(a), 3(a), 4(a)), a time point which is sufficient for observing IEG expression in the LA after LTP [27].


The NO-cGMP-PKG signaling pathway coordinately regulates ERK and ERK-driven gene expression at pre- and postsynaptic sites following LTP-inducing stimulation of thalamo-amygdala synapses.

Ping J, Schafe GE - Neural Plast. (2011)

High-frequency stimulation of the MGm/PIN promotes ERK-driven IEG expression in both the LA and MGm/PIN. (a) Placement of stimulation electrode and schematic of the experimental protocol. Rats were given HFS or LFS and sacrificed 2 hours after stimulation. (b) Images of Western blots for Arc/Arg3.1, c-Fos, EGR-1, and GAPDH from both LA (top) and MGm/PIN samples (bottom). (c) Mean (±SEM) percent IEG immunoreactivity from LA punches taken from rats given HFS (n = 9) or LFS (n = 9). (d) Mean (±SEM) percent IEG immunoreactivity from MGm/PIN punches taken from rats given HFS (n = 9) or LFS (n = 9). In each figure, IEG levels have been normalized to GAPDH for each sample, and IEG expression on the ipsilateral side has been expressed as a percentage of that on the contralateral side for each rat. *P < .05 relative to the ipsilateral side N.S. = not significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3065048&req=5

fig2: High-frequency stimulation of the MGm/PIN promotes ERK-driven IEG expression in both the LA and MGm/PIN. (a) Placement of stimulation electrode and schematic of the experimental protocol. Rats were given HFS or LFS and sacrificed 2 hours after stimulation. (b) Images of Western blots for Arc/Arg3.1, c-Fos, EGR-1, and GAPDH from both LA (top) and MGm/PIN samples (bottom). (c) Mean (±SEM) percent IEG immunoreactivity from LA punches taken from rats given HFS (n = 9) or LFS (n = 9). (d) Mean (±SEM) percent IEG immunoreactivity from MGm/PIN punches taken from rats given HFS (n = 9) or LFS (n = 9). In each figure, IEG levels have been normalized to GAPDH for each sample, and IEG expression on the ipsilateral side has been expressed as a percentage of that on the contralateral side for each rat. *P < .05 relative to the ipsilateral side N.S. = not significant.
Mentions: In our first series of experiments, we observed significant increases in ERK activation in the LA and MGm/PIN following HFS of the thalamo-LA pathway. In the present experiments, we used a combination of Western blotting and immunohistochemistry to examine whether LTP-inducing stimulation of thalamic input synapses to the LA regulate the ERK-driven IEGs Arc/Arg3.1, EGR-1 and c-Fos in the LA and the MGm/PIN. As before, anesthetized rats received either HFS or LFS of thalamic inputs to the LA and were sacrificed by decapitation 2 hours later (Figures 2(a), 3(a), 4(a)), a time point which is sufficient for observing IEG expression in the LA after LTP [27].

Bottom Line: Here, we show that LTP-inducing stimulation of thalamo-LA inputs regulates the activation of ERK and the expression of ERK-driven immediate early genes (IEGs) in both the LA and MGm/PIN.Further, we show that pharmacological blockade of NMDAR-driven synaptic plasticity, NOS activation, or PKG signaling in the LA significantly impairs high-frequency stimulation-(HFS-) induced ERK activation and IEG expression in both regions, while blockade of extracellular NO signaling in the LA impairs HFS-induced ERK activation and IEG expression exclusively in the MGm/PIN.These findings suggest that NMDAR-driven synaptic plasticity and NO-cGMP-PKG signaling within the LA coordinately regulate ERK-driven gene expression in both the LA and the MGm/PIN following LTP induction at thalamo-LA synapses, and that synaptic plasticity in the LA promotes ERK-driven transcription in MGm/PIN neurons via NO-driven "retrograde signaling".

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, Yale University, New Haven, CT 06520, USA.

ABSTRACT
Long-term potentiation (LTP) at thalamic input synapses to the lateral nucleus of the amygdala (LA) has been proposed as a cellular mechanism of the formation of auditory fear memories. We have previously shown that signaling via ERK/MAPK in both the LA and the medial division of the medial geniculate nucleus/posterior intralaminar nucleus (MGm/PIN) is critical for LTP at thalamo-LA synapses. Here, we show that LTP-inducing stimulation of thalamo-LA inputs regulates the activation of ERK and the expression of ERK-driven immediate early genes (IEGs) in both the LA and MGm/PIN. Further, we show that pharmacological blockade of NMDAR-driven synaptic plasticity, NOS activation, or PKG signaling in the LA significantly impairs high-frequency stimulation-(HFS-) induced ERK activation and IEG expression in both regions, while blockade of extracellular NO signaling in the LA impairs HFS-induced ERK activation and IEG expression exclusively in the MGm/PIN. These findings suggest that NMDAR-driven synaptic plasticity and NO-cGMP-PKG signaling within the LA coordinately regulate ERK-driven gene expression in both the LA and the MGm/PIN following LTP induction at thalamo-LA synapses, and that synaptic plasticity in the LA promotes ERK-driven transcription in MGm/PIN neurons via NO-driven "retrograde signaling".

Show MeSH
Related in: MedlinePlus