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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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Pharmacological blockade of PKG in the LA impairs ERK-driven IEG expression in both LA and MGm/PIN following HFS. (a) Images of Western blots for Arc/Arg3.1, c-Fos, EGR-1, and GAPDH from both LA (top) and MGm/PIN (bottom) samples. (b) Mean (±SEM) percent Arc/Arg3.1, c-Fos, and EGR-1 immunoreactivity from LA punches taken from rats given intra-LA infusion of ACSF (vehicle; n = 8) or 1 μg/side Rp-8-Br-PET-cGMPS (n = 8). (c) Mean (±SEM) percent Arc/Arg3.1, c-Fos and EGR-1 immunoreactivity from MGm/PIN punches taken from rats given intra-LA infusion of ACSF (vehicle; n = 8) or 1 μg/side Rp-8-Br-PET-cGMPS (n = 8). 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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fig9: Pharmacological blockade of PKG in the LA impairs ERK-driven IEG expression in both LA and MGm/PIN following HFS. (a) Images of Western blots for Arc/Arg3.1, c-Fos, EGR-1, and GAPDH from both LA (top) and MGm/PIN (bottom) samples. (b) Mean (±SEM) percent Arc/Arg3.1, c-Fos, and EGR-1 immunoreactivity from LA punches taken from rats given intra-LA infusion of ACSF (vehicle; n = 8) or 1 μg/side Rp-8-Br-PET-cGMPS (n = 8). (c) Mean (±SEM) percent Arc/Arg3.1, c-Fos and EGR-1 immunoreactivity from MGm/PIN punches taken from rats given intra-LA infusion of ACSF (vehicle; n = 8) or 1 μg/side Rp-8-Br-PET-cGMPS (n = 8). 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: The findings for rats infused with PKG inhibitor Rp-8-Br-PET-cGMPS are depicted in Figure 9(b)-9(c), and images of Western blots are presented in Figure 9(a). We observed significant elevations in the expression of Arc/Arg3.1, c-Fos, and EGR-1 protein expression in LA homogenates from vehicle-infused controls [Arc/Arg3.1: t(7) = 7.972. P < .05; c-Fos: t(7) = 3.686, P < .05; EGR-1: t(7) = 4.599, P < .05; Figure 9(b)]. In contrast, those rats given intra-LA infusion of Rp-8-Br-PET-cGMPS exhibited significantly impaired IEG expression in the LA [Arc/Arg3.1: t(6) = 1.688. P > .05; c-Fos: t(7) = 0.631, P > .05; EGR-1: t(7) = 1.287, P > .05; Figure 9(b)]. A similar pattern of findings was observed in the MGm/PIN (Figure 9(c)). Vehicle-infused controls exhibited significant elevations in the expression of Arc/Arg3.1, c-Fos, and EGR-1 protein expression in MGm/PIN homogenates [Arc/Arg3.1: t(7) = 7.972. P < .05; c-Fos: t(7) = 4.064, P < .05; EGR-1: t(7) = 4.901, P < .05; Figure 9(c)], while rats infused with the PKG inhibitor exhibited significantly impaired IEG expression in the MGm/PIN [Arc/Arg3.1: t(6) = 1.688. P > .05; c-Fos: t(7) = 1.101, P > .05; EGR-1: t(7) = 0.401, P > .05; Figure 9(c)].


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)

Pharmacological blockade of PKG in the LA impairs ERK-driven IEG expression in both LA and MGm/PIN following HFS. (a) Images of Western blots for Arc/Arg3.1, c-Fos, EGR-1, and GAPDH from both LA (top) and MGm/PIN (bottom) samples. (b) Mean (±SEM) percent Arc/Arg3.1, c-Fos, and EGR-1 immunoreactivity from LA punches taken from rats given intra-LA infusion of ACSF (vehicle; n = 8) or 1 μg/side Rp-8-Br-PET-cGMPS (n = 8). (c) Mean (±SEM) percent Arc/Arg3.1, c-Fos and EGR-1 immunoreactivity from MGm/PIN punches taken from rats given intra-LA infusion of ACSF (vehicle; n = 8) or 1 μg/side Rp-8-Br-PET-cGMPS (n = 8). 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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Related In: Results  -  Collection

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fig9: Pharmacological blockade of PKG in the LA impairs ERK-driven IEG expression in both LA and MGm/PIN following HFS. (a) Images of Western blots for Arc/Arg3.1, c-Fos, EGR-1, and GAPDH from both LA (top) and MGm/PIN (bottom) samples. (b) Mean (±SEM) percent Arc/Arg3.1, c-Fos, and EGR-1 immunoreactivity from LA punches taken from rats given intra-LA infusion of ACSF (vehicle; n = 8) or 1 μg/side Rp-8-Br-PET-cGMPS (n = 8). (c) Mean (±SEM) percent Arc/Arg3.1, c-Fos and EGR-1 immunoreactivity from MGm/PIN punches taken from rats given intra-LA infusion of ACSF (vehicle; n = 8) or 1 μg/side Rp-8-Br-PET-cGMPS (n = 8). 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: The findings for rats infused with PKG inhibitor Rp-8-Br-PET-cGMPS are depicted in Figure 9(b)-9(c), and images of Western blots are presented in Figure 9(a). We observed significant elevations in the expression of Arc/Arg3.1, c-Fos, and EGR-1 protein expression in LA homogenates from vehicle-infused controls [Arc/Arg3.1: t(7) = 7.972. P < .05; c-Fos: t(7) = 3.686, P < .05; EGR-1: t(7) = 4.599, P < .05; Figure 9(b)]. In contrast, those rats given intra-LA infusion of Rp-8-Br-PET-cGMPS exhibited significantly impaired IEG expression in the LA [Arc/Arg3.1: t(6) = 1.688. P > .05; c-Fos: t(7) = 0.631, P > .05; EGR-1: t(7) = 1.287, P > .05; Figure 9(b)]. A similar pattern of findings was observed in the MGm/PIN (Figure 9(c)). Vehicle-infused controls exhibited significant elevations in the expression of Arc/Arg3.1, c-Fos, and EGR-1 protein expression in MGm/PIN homogenates [Arc/Arg3.1: t(7) = 7.972. P < .05; c-Fos: t(7) = 4.064, P < .05; EGR-1: t(7) = 4.901, P < .05; Figure 9(c)], while rats infused with the PKG inhibitor exhibited significantly impaired IEG expression in the MGm/PIN [Arc/Arg3.1: t(6) = 1.688. P > .05; c-Fos: t(7) = 1.101, P > .05; EGR-1: t(7) = 0.401, P > .05; Figure 9(c)].

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