Long-Lasting LTP Requires Neither Repeated Trains for Its Induction Nor Protein Synthesis for Its Development

Villers, Arnauld; Godaux, Emile; Ris, Laurence

doi:10.1371/journal.pone.0040823

Cited by 30 publications

(28 citation statements)

References 78 publications

(98 reference statements)

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“…However, in our case, as LTP had been shown to be resistant to the presence of protein synthesis inhibitors (Villers et al 2012), this effect was not present. Conversely, a specific form of potentiation was observed in slices prepared from mutant mice and incubated with rapamycin.…”

Section: Rapamycin Effectcontrasting

confidence: 53%

Long-term potentiation can be induced in the CA1 region of hippocampus in the absence of αCaMKII T286-autophosphorylation

2014

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a-calcium/calmodulin-dependent protein kinase (aCaMKII) T286-autophosphorylation provides a short-term molecular memory that was thought to be required for LTP and for learning and memory. However, it has been shown that learning can occur in aCaMKII-T286A mutant mice after a massed training protocol. This raises the question of whether there might be a form of LTP in these mice that can occur without T286 autophosphorylation. In this study, we confirmed that in CA1 pyramidal cells, LTP induced in acute hippocampal slices, after a recovery period in an interface chamber, is strictly dependent on postsynaptic aCaMKII autophosphorylation. However, we demonstrated that aCaMKII-autophosphorylation-independent plasticity can occur in the hippocampus but at the expense of synaptic specificity. This nonspecific LTP was observed in mutant and wild-type mice after a recovery period in a submersion chamber and was independent of NMDA receptors. Moreover, when slices prepared from mutant mice were preincubated during 2 h with rapamycin, high-frequency trains induced a synapse-specific LTP which was added to the nonspecific LTP. This specific LTP was related to an increase in the duration and the amplitude of NMDA receptor-mediated response induced by rapamycin.The formation of memories is believed to be achieved through strengthening of synaptic communication between two simultaneously active neurons, a phenomenon called long-term potentiation (LTP). For several years, numerous studies have sought to better understand the molecular mechanisms of synaptic plasticity and LTP, and in particular the role of calcium-calmodulin-dependent protein kinase II (CaMKII), one of the most important postsynaptic components in glutamatergic synapses. Indeed, CaMKII is both necessary and sufficient for LTP induction. The application of CaMKII inhibitors, such as KN-62 or KN-93, or genetic disruption of the CaMKII gene can block LTP (Malinow et al. 1989;Otmakhov et al. 1997;Hinds et al. 1998;Yamagata et al. 2009). Conversely, the injection or viral expression of a constitutively active form of CaMKII leads to the improvement of spatial memory (Poulsen et al. 2007), in enhancement of AMPAR-mediated synaptic transmission and occludes further induction of LTP (McGladeMcCulloh et al. 1993;Pettit et al. 1994;Lledo et al. 1995). This enhancement in AMPAR conductance has been proposed to occur through an increase in synaptic trafficking of GluA1 subunits, as well as phosphorylation of GluA1 at Ser831 (Shi et al. 1999;Hayashi et al. 2000;Broutman and Baudry 2001;Esteban et al. 2003;Oh et al. 2006). Besides its role in synaptic transmission, CaMKII is also involved in the structural plasticity of spines, and more specifically in activity-dependent spine growth following NMDAR activation (Okamoto et al. 2009;Pi et al. 2010). Moreover, it seems that CaMKII-dependent processes involved in hippocampal LTP in CA1 synapses are quite general since the kinase also affects in vivo plasticity in different brain regions (Wu and Cline 1998;Zou and Cline 1999). ...

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Section: Rapamycin Effectcontrasting

confidence: 53%

Long-term potentiation can be induced in the CA1 region of hippocampus in the absence of αCaMKII T286-autophosphorylation

2014

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“…These results and other recent reports (Abbas, 2013;Abbas et al, 2009;Villers et al, 2012) are at odds with many published studies showing that enduring LTP was blocked by protein synthesis inhibitors (Fonseca et al, 2006a;Frey et al, 1988;Osten et al, 1996;Tsokas et al, 2005). Thus, we conducted additional experiments to determine potential sources for the discrepancy.…”

mentioning

confidence: 58%

“…First, our LTP experiments do not support for the protein synthesis hypothesis. We do not stand alone on this matter (Abbas, 2013;Abbas et al, 2009Abbas et al, , 2011Pang et al, 2004;Villers et al, 2012). However, it is important to note that we do not simply report that inhibiting protein synthesis failed to prevent the lasting form of LTP.…”

Section: Discussionmentioning

confidence: 83%

“…One set indicates that at least some of the memory impairments produced by protein synthesis inhibitors may be the result of their offtarget effects (e.g., Canal et al, 2007;Sharma et al, 2012). Another body of results indicates that memories and LTP can indeed persist even in the face of severe inhibition of protein synthesis (Abbas, 2013;Abbas et al, 2009Abbas et al, , 2011Abraham and Williams, 2008;Fonseca et al, 2006b;Martinez et al, 1981;Pang et al, 2004;Staubli et al, 1985;Villers et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Protein synthesis and consolidation of memory-related synaptic changes

2015

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Published findings and new results described here challenge this idea. Protein synthesis inhibitors did not prevent Theta Bust Stimulation (TBS) from producing extremely stable longterm potentiation (LTP) in experiments using standard hippocampal slice protocols. However, the inhibitors were effective under conditions that likely depleted protein levels prior to attempts to induce the potentiation effect. Experiments showed that induction of LTP at one input, and thus a prior episode of protein synthesis, eliminated the effects of inhibitors on potentiation of a second input even in depleted slices. These observations suggest that a primary role of translation and transcription processes initiated by learning events is to prepare neurons to support future learning. Other work has provided support for an alternative theory of consolidation. Specifically, if the synaptic changes that support memory are to endure, learning events/TBS must engage a complex set of signaling processes that reorganize and re-stabilize the spine actin cytoskeleton. This is accomplished in fast (10 min) and slow (50 min) stages with the first requiring integrin activation and the second a recovery of integrin functioning. These results align with, and provide mechanisms for, the long-held view that memories are established and consolidated over a set of temporally distinct phases.

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“…1 h) following induction [8][9][10]. Although rarely cited, there are also a number of very well-controlled studies that have found no effect of protein synthesis inhibition for up to 8 h following the tetanus [11,12]. Finally, the fact that well over a 100 proteins have been claimed to be involved in LTP has led some investigators to lament that understanding this phenomenon will remain forever elusive [13].…”

Section: Multiple Forms Of Long-term Potentiationmentioning

confidence: 99%

Expression mechanisms underlying long-term potentiation: a postsynaptic view, 10 years on

Granger

2014

Phil. Trans. R. Soc. B

105

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This review focuses on the research that has occurred over the past decade which has solidified a postsynaptic expression mechanism for long-term potentiation (LTP). However, experiments that have suggested a presynaptic component are also summarized. It is argued that the pairing of glutamate uncaging onto single spines with postsynaptic depolarization provides the final and most elegant demonstration of a postsynaptic expression mechanism for NMDA receptor-dependent LTP. The fact that the magnitude of this LTP is similar to that evoked by pairing synaptic stimulation and depolarization leaves little room for a substantial presynaptic component. Finally, recent data also require a revision in our thinking about the way AMPA receptors (AMPARs) are recruited to the postsynaptic density during LTP. This recruitment is independent of subunit type, but does require an adequate reserve pool of extrasynaptic receptors.

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Long-Lasting LTP Requires Neither Repeated Trains for Its Induction Nor Protein Synthesis for Its Development

Cited by 30 publications

References 78 publications

Long-term potentiation can be induced in the CA1 region of hippocampus in the absence of αCaMKII T286-autophosphorylation

Long-term potentiation can be induced in the CA1 region of hippocampus in the absence of αCaMKII T286-autophosphorylation

Protein synthesis and consolidation of memory-related synaptic changes

Expression mechanisms underlying long-term potentiation: a postsynaptic view, 10 years on

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