Transgenic Inhibition of Neuronal Protein Kinase A Activity Facilitates Fear Extinction

Isiegas, Carolina; Park, Alice; Kandel, Eric R.; Abel, Ted; Lattal, K. Matthew

doi:10.1523/jneurosci.2743-06.2006

Cited by 69 publications

(65 citation statements)

References 65 publications

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“…Consistent with earlier reports, the employed manipulations did not affect conditioning and retrieval (Selcher et al, 2001) or reconsolidation (Fischer et al, 2007;Chen et al, 2005;Isiegas et al, 2006) of the fear memory, suggesting their specific contribution to extinction learning.…”

Section: Discussionsupporting

confidence: 90%

“…It should be noted, however, that unlike short-term PKA inhibition, long-term upregulation (Wang et al, 2004) or downregulation (Isiegas et al, 2006) of PKA signaling by genetic manipulations affecting both baseline and inducible PKA activity in several brain areas and over a long period of time might prevent or enhance fear extinction, respectively. Given that the effects of genetic PKA inactivation predominantly affected within session extinction (Isiegas et al, 2006), it is also possible that longer extinction trials are required for the induction of the PKA pathway.…”

Section: Discussionmentioning

confidence: 99%

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Regulatory Mechanisms of Fear Extinction and Depression-Like Behavior

Tronson

Schrick

Fischer

et al. 2007

Neuropsychopharmacol

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Human anxiety is frequently accompanied by depression, and when they co-occur both conditions exhibit greater severity and resistance to treatment. Little is known, however, about the molecular processes linking these emotional and mood disorders. Based on previously reported phosphorylation patterns of extracellular signal-regulated kinase (ERK) in the brain, we hypothesized that ERK's upstream activators intertwine fear and mood regulation through their hippocampal actions. We tested this hypothesis by studying the upstream regulation of ERK signaling in behavioral models of fear and depression. Wild-type and ERK1-deficient mice were used to study the dorsohippocampal actions of the putative ERK activators: mitogen-activated and extracellular signal-regulated kinase (MEK), protein kinase C (PKC), and cAMP-dependent protein kinase (PKA). Mice lacking ERK1 exhibited enhanced fear extinction and reduced depression caused by overactivation of ERK2. Both behaviors were reversed by inhibition of MEK, however the extinction phenotype depended on hippocampal, whereas the depression phenotype predominantly involved extrahippocampal MEK. Unexpectedly, inhibition of PKC accelerated extinction and decreased depression by ERK-independent mechanisms, whereas inhibition of PKA did not produce detectable molecular or behavioral effects in the employed paradigm. These results indicate that, contrary to fear conditioning but similar to mood stabilization, extinction of fear required upregulation of MEK/ERK and downregulation of ERK-independent PKC signaling. The dissociation of these pathways may thus represent a common mechanism for fear and mood regulation, and a potential therapeutic option for comorbid anxiety and depression.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Regulatory Mechanisms of Fear Extinction and Depression-Like Behavior

Tronson

Schrick

Fischer

et al. 2007

Neuropsychopharmacol

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“…Gas overexpressing animals exhibited a deficit in one-trial fear learning which could be overcome by multiple learning trials and corrected by application of a PKA inhibitor [48]. In keeping, we found that Ophn1-deficient mice show normal fear learning in a multitrial learning paradigm, but severely compromised extinction learning, another form of learning depending on cAMP/ PKA signalling [49]. Interestingly, genetic inhibition of PKA in the forebrain was shown to facilitate learning of fear extinction in mice [49], with a pronounced effect within extinction sessions, suggesting a crucial role of PKA signalling in some fast CREB independent and behaviourally relevant plasticity processes such as the one reported here.…”

Section: Discussionsupporting

confidence: 75%

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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“…To address the roles of ␣CaMKII signaling in the two distinct processes of extinction, mice were subjected to a single but longer re-exposure to the conditioning context in the absence of foot shock, which has been reported to favor the development of rapid and dramatic extinction of contextually conditioned fear (Suzuki et al 2004;Isiegas et al 2006). Consistent with these findings, we also found that a single 30-min re-exposure of wild-type control mice to the chamber 24 h after training with one CS-US pairing resulted in a significant reduction of contextual freezing within the long extinction session (F (4,105) = 6.99, P < 0.05) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Autophosphorylation of αCaMKII is differentially involved in new learning and unlearning mechanisms of memory extinction

Kimura¹,

Silva²,

Ohno³

2008

Learn. Mem.

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Accumulating evidence indicates the key role of ␣-calcium/calmodulin-dependent protein kinase II (␣CaMKII) in synaptic plasticity and learning, but it remains unclear how this kinase participates in the processing of memory extinction. Here, we investigated the mechanism by which ␣CaMKII may mediate extinction by using heterozygous knock-in mice with a targeted T286A mutation that prevents the autophosphorylation of this kinase (␣CaMKII T286A+/-). Remarkably, partial reduction of ␣CaMKII function due to the T286A +/-mutation prevented the development of extinction without interfering with initial hippocampus-dependent memory formation as assessed by contextual fear conditioning and the Morris water maze. It is hypothesized that the mechanism of extinction may differ depending on the interval at which extinction training is started, being more akin to "new learning" at longer intervals and "unlearning" or "erasure" at shorter intervals. Consistent with this hypothesis, we found that extinction conducted 24 h, but not 15 min, after contextual fear training showed spontaneous recovery (reappearance of extinguished freezing responses) 21 d following the extinction, representing behavioral evidence for new learning and unlearning mechanisms underlying extinction 24 h and 15 min post-training, respectively. Importantly, the ␣CaMKII T286A+/-mutation blocked new learning of contextual fear memory extinction, whereas it did not interfere with unlearning processes. Our results demonstrate a genetic dissociation of new learning and unlearning mechanisms of extinction, and suggest that ␣CaMKII is responsible for extinguishing memories specifically through new learning mechanisms.

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Transgenic Inhibition of Neuronal Protein Kinase A Activity Facilitates Fear Extinction

Cited by 69 publications

References 65 publications

Regulatory Mechanisms of Fear Extinction and Depression-Like Behavior

Regulatory Mechanisms of Fear Extinction and Depression-Like Behavior

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

Autophosphorylation of αCaMKII is differentially involved in new learning and unlearning mechanisms of memory extinction

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