Regulation of amygdalar PKA by β-arrestin-2/phosphodiesterase-4 complex is critical for fear conditioning

Li, Yuting; Li, Hao‐Hong; Liu, Xing; Bao, Guobin; Tao, Yezheng; Wu, Ziyan; Xia, Peng; Wu, Chunfu; Li, Baoming; Ma, Lan

doi:10.1073/pnas.0906941106

Cited by 31 publications

(22 citation statements)

References 50 publications

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“…Similar results were observed in GSK3 mutant mice, which display a 50% reduction in the expression of this kinase (Hoeflich et al, 2000). With respect to β-arrestin-2, recent findings show that this protein might be also involved in neurogenesisdependent and -independent mechanisms Li et al, 2009). Using the "CORT model", it was shown that fluoxetine reversed the neurogenic deficit induced by glucocorticoid elevation and restored expression of β-arrestin-1 and -2 that were blunted by chronic corticosterone ).…”

Section: Current Hypotheses On the Molecular And Cellular Bases Of Nosupporting

confidence: 65%

Non-Response to Initial Antidepressant Therapy

Guilloux¹,

David²,

Samuels³

et al. 2012

Psychology - Selected Papers

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Section: Current Hypotheses On the Molecular And Cellular Bases Of Nosupporting

confidence: 65%

Non-Response to Initial Antidepressant Therapy

Guilloux¹,

David²,

Samuels³

et al. 2012

Psychology - Selected Papers

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“…It is well established that cAMP signalling plays a central role in neuronal plasticity and learning [43,44]. This includes both acute effects mediated through activation of PKA and long-term changes involving transcriptional regulation [45].…”

Section: Discussionmentioning

confidence: 99%

“…Either too much activity or too little activity results in learning deficits, suggesting the existence of complex compensatory feedback mechanisms. Accordingly, modulators of cAMP phosphodiesterases (PDEs) have been successfully used to correct for memory deficits induced by up-or downregulations of PKA signalling [43,48]. Mice expressing a constitutively active form of Gas in forebrain neurons exhibit lower brain cAMP levels because of an increase in PKA-dependent PDE activity [48].…”

Section: Discussionmentioning

confidence: 99%

Lack of the presynaptic RhoGAP protein oligophrenin1 leads to cognitive disabilities through dysregulation of the cAMP/PKA signalling pathway

Khelfaoui

Gambino

Houbaert

et al. 2014

Phil. Trans. R. Soc. B

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Loss-of-function mutations in the gene encoding for the RhoGAP protein of oligophrenin-1 (OPHN1) lead to cognitive disabilities (CDs) in humans, yet the underlying mechanisms are not known. Here, we show that in mice constitutive lack of Ophn1 is associated with dysregulation of the cyclic adenosine monophosphate/phosphate kinase A (cAMP/PKA) signalling pathway in a brain-area-specific manner. Consistent with a key role of cAMP/PKA signalling in regulating presynaptic function and plasticity, we found that PKA-dependent presynaptic plasticity was completely abolished in affected brain regions, including hippocampus and amygdala. At the behavioural level, lack of OPHN1 resulted in hippocampus- and amygdala-related learning disabilities which could be fully rescued by the ROCK/PKA kinase inhibitor fasudil. Together, our data identify OPHN1 as a key regulator of presynaptic function and suggest that, in addition to reported postsynaptic deficits, loss of presynaptic plasticity contributes to the pathophysiology of CDs.

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“…Fear conditioning activates the PKA signaling pathway that is significant inhibited by extinction (Isiegas et al, 2006;Li et al, 2009;Moita et al, 2002;Schafe et al, 1999). Genetic inhibition of PKA activity or pharmacological inhibition of the anchoring of PKA to A-kinase anchoring proteins facilitated extinction learning (Nijholt et al, 2008).…”

Section: Mechanism That Underlies the Role Of Hippocampal Ne In The Pmentioning

confidence: 99%

Delayed Noradrenergic Activation in the Dorsal Hippocampus Promotes the Long-Term Persistence of Extinguished Fear

Chai

Liu

Xue

et al. 2014

Neuropsychopharmacol

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Fear extinction has been extensively studied, but little is known about the molecular processes that underlie the persistence of extinction long-term memory (LTM). We found that microinfusion of norepinephrine (NE) into the CA1 area of the dorsal hippocampus during the early phase (0 h) after extinction enhanced extinction LTM at 2 and 14 days after extinction. Intra-CA1 infusion of NE during the late phase (12 h) after extinction selectively promoted extinction LTM at 14 days after extinction that was blocked by the b-receptor antagonist propranolol, protein kinase A (PKA) inhibitor Rp-cAMPS, and protein synthesis inhibitors anisomycin and emetine. The phosphorylation levels of PKA, cyclic adenosine monophosphate response element-binding protein (CREB), GluR1, and the membrane GluR1 level were increased by NE during the late phase after extinction that was also blocked by propranolol and Rp-cAMPS. These results suggest that the enhancement of extinction LTM persistence induced by NE requires the activation of the b-receptor/PKA/CREB signaling pathway and membrane GluR1 trafficking. Moreover, extinction increased the phosphorylation levels of Erk1/2, CREB, and GluR1, and the membrane GluR1 level during the late phase, and anisomycin/emetine alone disrupted the persistence of extinction LTM, indicating that the persistence of extinction LTM requires late-phase protein synthesis in the CA1. Propranolol and Rp-cAMPS did not completely disrupt the persistence of extinction LTM, suggesting that another b-receptor/PKA-independent mechanism underlies the persistence of extinction LTM. Altogether, our results showed that enhancing hippocampal noradrenergic activity during the late phase after extinction selectively promotes the persistence of extinction LTM.

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Regulation of amygdalar PKA by β-arrestin-2/phosphodiesterase-4 complex is critical for fear conditioning

Cited by 31 publications

References 50 publications

Non-Response to Initial Antidepressant Therapy

Non-Response to Initial Antidepressant Therapy

Lack of the presynaptic RhoGAP protein oligophrenin1 leads to cognitive disabilities through dysregulation of the cAMP/PKA signalling pathway

Delayed Noradrenergic Activation in the Dorsal Hippocampus Promotes the Long-Term Persistence of Extinguished Fear

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