CREB's control of intrinsic and synaptic plasticity: implications for CREB-dependent memory models

Benito, Eva; Barco, Ángel

doi:10.1016/j.tins.2010.02.001

Cited by 386 publications

(266 citation statements)

References 86 publications

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“…Because CREB decreases the sAHP (Viosca et al, 2009;Benito and Barco, 2010), we considered the possibility that a higher intrinsic excitability confers a competitive advantage to LA neurons. We could investigate this possibility with our model because it is endowed with three types of principal cells with high (type A, 50%), intermediate (type B, 30%), or low (type C, 20%) spike frequency adaptation (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…However, when CREB was overexpressed (CREB ϩ ) or downregulated (CREB Ϫ ) in LA, the proportion of LA neurons recruited into the memory trace did not change, suggesting that the assignment of particular LA neurons to the memory trace involves a competitive process (Han et al, 2007). Consistent with this, CREB enhances the intrinsic excitability of principal cells by inhibiting the slow afterhyperpolarization (sAHP) current (Viosca et al, 2009;Benito and Barco, 2010), without altering their membrane potential, input resistance, or spike shape . Moreover, the latter study suggested that CREB increases the likelihood that principal cells will become part of the fear memory by enhancing their intrinsic excitability.…”

Section: Introductionmentioning

confidence: 98%

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Assignment of Model Amygdala Neurons to the Fear Memory Trace Depends on Competitive Synaptic Interactions

2013

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We used biophysical modeling to examine a fundamental, yet unresolved, question regarding how particular lateral amygdala (LA) neurons are assigned to fear memory traces. This revealed that neurons with high intrinsic excitability are more likely to be integrated into the memory trace, but that competitive synaptic interactions also play a critical role. Indeed, when the ratio of intrinsically excitable cells was increased or decreased, the number of plastic cells remained relatively constant. Analysis of the connectivity of plastic and nonplastic cells revealed that subsets of principal LA neurons effectively band together by virtue of their excitatory interconnections to suppress plasticity in other principal cells via the recruitment of inhibitory interneurons. IntroductionClassical fear conditioning is an experimental paradigm used to investigate how animals learn to fear new stimuli by experience. In this model, a neutral sensory stimulus [conditioned stimulus (CS)] acquires the ability to elicit fear responses after a few pairings with a noxious stimulus [unconditioned stimulus (US)]. While there is evidence that fear conditioning induces widespread synaptic plasticity in the brain, including at thalamic and cortical levels (Letzkus et al., 2011; Weinberger, 2011), there are also data indicating that the dorsal portion of the lateral amygdala (LAd) is a critical site of plasticity for the storage of pavlovian fear memories (LeDoux, 2000; Pape and Paré, 2010). What is less clear is how particular LAd neurons are assigned to the fear memory trace. Indeed, relatively few LAd neurons (25%) acquire an increased responsiveness to stimuli predicting adverse outcomes (Quirk et al., 1995;Repa et al., 2001; Rumpel et al., 2005), even though most receive the necessary inputs (Han et al., 2007).In a previous study, we developed a biophysical LAd model that reproduced experimental findings regarding the cellular correlates of fear conditioning in LA ( Fig. 1A-D; Kim et al., 2013). We used it to examine whether fear memories depend on (1) training-induced increases in the responsiveness of thalamic and cortical neurons projecting to LA, (2) plasticity at the synapses they form in LA, and/or (3) plasticity at synapses between LA neurons. These tests revealed that training-induced increases in the responsiveness of afferent neurons are required for fear memory formation. However, once the memory has been formed, this factor is no longer required because the efficacy of the synapses that thalamic and cortical neurons form with LA cells has augmented enough to maintain the memory. In contrast, plasticity at synapses between LA neurons was found to play a minor role in maintaining the fear memory.In the present study, we use the model to examine how particular LA neurons are assigned to fear memory traces. Previously, it was reported that LA cells expressing high levels of activated cAMP response element-binding protein (CREB; hereafter "activated CREB" is denoted as "CREB") are preferentially recruited into the memory trace...

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Assignment of Model Amygdala Neurons to the Fear Memory Trace Depends on Competitive Synaptic Interactions

2013

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“…To explore the molecular mechanisms that may underlie synapse and memory impairments, we measured CREB, a crucial functional protein for memory formation and consolidation (35). We found that overexpression of hTau in hippocampal neurons cultured for 12 div remarkably decreased the phosphorylation level of CREB at Ser133, although the total CREB was elevated in neuronal lysates ( Fig.…”

Section: Overexpression Of Htau In Hippocampal Neurons Induces Memorymentioning

confidence: 95%

Tau accumulation induces synaptic impairment and memory deficit by calcineurin-mediated inactivation of nuclear CaMKIV/CREB signaling

Yin

Gao

Wang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

146

119

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Intracellular accumulation of wild-type tau is a hallmark of sporadic Alzheimer's disease (AD), but the molecular mechanisms underlying tau-induced synapse impairment and memory deficit are poorly understood. Here we found that overexpression of human wild-type full-length tau (termed hTau) induced memory deficits with impairments of synaptic plasticity. Both in vivo and in vitro data demonstrated that hTau accumulation caused remarkable dephosphorylation of cAMP response element binding protein (CREB) in the nuclear fraction. Simultaneously, the calcium-dependent protein phosphatase calcineurin (CaN) was up-regulated, whereas the calcium/ calmodulin-dependent protein kinase IV (CaMKIV) was suppressed. Further studies revealed that CaN activation could dephosphorylate CREB and CaMKIV, and the effect of CaN on CREB dephosphorylation was independent of CaMKIV inhibition. Finally, inhibition of CaN attenuated the hTau-induced CREB dephosphorylation with improved synapse and memory functions. Together, these data indicate that the hTau accumulation impairs synapse and memory by CaN-mediated suppression of nuclear CaMKIV/CREB signaling. Our findings not only reveal new mechanisms underlying the hTau-induced synaptic toxicity, but also provide potential targets for rescuing tauopathies.is the most common neurodegenerative disorder characterized clinically by progressive memory loss (1). The extracellular precipitation of β-amyloid (Aβ) (2), intracellular tau accumulation forming neurofibrillary tangles (3), and profound synapse degeneration are hallmark pathologies in AD brains (4, 5). Studies show that formation of neurofibrillary tangles is positively correlated with the degree of dementia symptoms (6), and the Aβ toxicity needs the presence of tau (7). These data suggest a crucial role of tau accumulation in neurodegeneration and the cognitive impairments in patients with AD. As a cytoskeleton protein, how tau accumulation causes memory deficits is not fully understood.Synapse is the fundamental unit for learning and memory. Dysfunction of synaptic connections is recognized as the cause of memory impairments, and significant synapse loss has been observed in mild cognitive impairment (MCI) and in earlier stages of AD (8). In AD mouse models, synapse impairments appear before the onset of memory deficit (9), whereas amelioration of synapse loss by administration of estradiol preserves cognitive functions (10). Earlier investigations into AD-related synaptic damages have been mainly focused on the toxic effects of Aβ (11). Recently, an emerging role of tau in synaptic impairment has been shown (12). For instance, overexpression of human mutant tau in mice induces synaptic degeneration even in the absence of tangles (13, 14) and reducing endogenous tau in mouse models carrying the mutated amyloid precursor protein (APP) prevents the cognitive deficits and synaptic loss (15).Among many structural or functional proteins involved in synapse development and memory formation, cAMP response element binding protein (CREB) is...

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“…BDNF mRNA expression is reduced by stress, leading to impaired hippocampal synaptic plasticity [79] through G-protein coupled receptors (GPCRs) [83] . Chronic antidepressant administration enhances the coupling of GPCRs to adenylyl cyclase, PKA activation, and expression of CREB [19] .…”

Section: Brain-derived Neurotrophic Factormentioning

confidence: 99%

“…Modulatory neurotransmitters such as 5-HT, NE, and dopamine increase the intracellular cyclic adenosine monophosphate (cAMP) concentration and activate cAMP-dependent protein kinase (PKA) through G-protein coupled receptors (GPCRs) [83] . Chronic antidepressant administration enhances the coupling of GPCRs to adenylyl cyclase, PKA activation, and expression of CREB [19] .…”

Section: Creb Signaling Cascade Under Monoamine-based Antidepressantsmentioning

confidence: 99%

Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

et al. 2014

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Depression is a devastating psychiatric disorder widely attributed to defi cient monoaminergic signaling in the central nervous system. However, most clinical antidepressants enhance monoaminergic neurotransmission with little delay but require 4−8 weeks to reach therapeutic efficacy, a paradox suggesting that the monoaminergic hypothesis of depression is an oversimplifi cation. In contrast to the antidepressants targeting the monoaminergic system, a single dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine produces rapid (within 2 h) and sustained (over 7 days) antidepressant effi cacy in treatment-resistant patients. Glutamatergic transmission mediated by NMDARs is critical for experience-dependent synaptic plasticity and learning, processes that can be modifi ed indirectly by the monoaminergic system. To better understand the mechanisms of action of the new antidepressants like ketamine, we review and compare the monoaminergic and glutamatergic antidepressants, with emphasis on neural plasticity. The pathogenesis of depression may involve maladaptive neural plasticity in glutamatergic circuits that may serve as a new class of targets to produce rapid antidepressant effects.Keywords: depression; stress; neural plasticity; glutamatergic transmission; monoamine-based antidepressant; ketamine IntroductionDepression is a common psychiatric disorder, with prevalence rates of 19% in Beirut and 16.2% in the UnitedStates [1] . Depression is also one of the leading causes of severe mental disability, suicide, and socioeconomic burden, and its diagnosis sometimes relies on selfreported symptoms in the major depressive inventory [2,3] .The pathogenesis of depression is still not clear, and currently available antidepressants are far from satisfactory.Most antidepressants target the monoaminergic system [4] ; however, 30%-40% of patients are resistant to monoaminebased antidepressants (remittance rates of 13% to 36.8% with citalopram [5] ), and a clinically significant reduction of depressive symptoms in responders usually requires 4−8 weeks of daily treatment [6] . These limitations result in a large proportion of patients at high risk of suicide even after diagnosis. Thus, it is necessary to search for new antidepressants outside the monoaminergic system. R ecent clinical studies have demonstrated that a single dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine has rapid antidepressant efficacy within 2 h that can be sustained for over 7 days in patients with treatment-resistant depression [7,8] . This finding suggests that depression could be directly associated with defi cits in glutamatergic synaptic transmission and plasticity. The monoaminergic hypothesis of depression, based on the efficacy of antidepressants that enhance monoaminergic transmission and signaling, has dominated the field of depression research for nearly half a century.However, the primacy of monoaminergic dysfunction in depression is inconsistent with the delay between enhancement of synaptic monoamines confer...

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CREB's control of intrinsic and synaptic plasticity: implications for CREB-dependent memory models

Cited by 386 publications

References 86 publications

Assignment of Model Amygdala Neurons to the Fear Memory Trace Depends on Competitive Synaptic Interactions

Assignment of Model Amygdala Neurons to the Fear Memory Trace Depends on Competitive Synaptic Interactions

Tau accumulation induces synaptic impairment and memory deficit by calcineurin-mediated inactivation of nuclear CaMKIV/CREB signaling

Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

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