Formation and Maintenance of Robust Long-Term Information Storage in the Presence of Synaptic Turnover.
Ontology highlight
ABSTRACT:
SUBMITTER: Fauth M
PROVIDER: S-EPMC4699846 | biostudies-literature | 2015 Dec
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Memory can last a lifetime, yet synaptic contacts that contribute to the storage of memory are composed of proteins that have much shorter lifetimes. A physiological model of memory formation, long-term potentiation (LTP), has a late protein-synthesis-dependent phase (L-LTP) that can last for many hours in slices or even for days in vivo. Could the activity-dependent synthesis of new proteins account for the persistence of L-LTP and memory? Here, we examine the proposal that a self-sustaining regulation of translation can form a bistable switch that can persistently regulate the on-site synthesis of plasticity-related proteins. We show that an alpha CaMKII-CPEB1 molecular pair can operate as a bistable switch. Our results imply that L-LTP should produce an increase in the total amount of alpha CaMKII at potentiated synapses. This study also proposes an explanation for why the application of protein synthesis and alphaCaMKII inhibitors at the induction and maintenance phases of L-LTP result in very different outcomes.
| S-EPMC2710869 | biostudies-other
Project description:Chemical synapses contain multitudes of proteins, which in common with all proteins, have finite lifetimes and therefore need to be continuously replaced. Given the huge numbers of synaptic connections typical neurons form, the demand to maintain the protein contents of these connections might be expected to place considerable metabolic demands on each neuron. Moreover, synaptic proteostasis might differ according to distance from global protein synthesis sites, the availability of distributed protein synthesis facilities, trafficking rates and synaptic protein dynamics. To date, the turnover kinetics of synaptic proteins have not been studied or analyzed systematically, and thus metabolic demands or the aforementioned relationships remain largely unknown. In the current study we used dynamic Stable Isotope Labeling with Amino acids in Cell culture (SILAC), mass spectrometry (MS), Fluorescent Non-Canonical Amino acid Tagging (FUNCAT), quantitative immunohistochemistry and bioinformatics to systematically measure the metabolic half-lives of hundreds of synaptic proteins, examine how these depend on their pre/postsynaptic affiliation or their association with particular molecular complexes, and assess the metabolic load of synaptic proteostasis. We found that nearly all synaptic proteins identified here exhibited half-lifetimes in the range of 2-5 days. Unexpectedly, metabolic turnover rates were not significantly different for presynaptic and postsynaptic proteins, or for proteins for which mRNAs are consistently found in dendrites. Some functionally or structurally related proteins exhibited very similar turnover rates, indicating that their biogenesis and degradation might be coupled, a possibility further supported by bioinformatics-based analyses. The relatively low turnover rates measured here (?0.7% of synaptic protein content per hour) are in good agreement with imaging-based studies of synaptic protein trafficking, yet indicate that the metabolic load synaptic protein turnover places on individual neurons is very substantial.
| S-EPMC3642143 | biostudies-literature
Project description:Long-term memory (LTM) formation requires new protein synthesis and new gene expression. Based on our work in Aplysia, we hypothesized that the rRNA genes, stimulation-dependent targets of the enzyme Poly(ADP-ribose) polymerase-1 (PARP-1), are primary effectors of the activity-dependent changes in synaptic function that maintain synaptic plasticity and memory. Using electrophysiology, immunohistochemistry, pharmacology and molecular biology techniques, we show here, for the first time, that the maintenance of forskolin-induced late-phase long-term potentiation (L-LTP) in mouse hippocampal slices requires nucleolar integrity and the expression of new rRNAs. The activity-dependent upregulation of rRNA, as well as L-LTP expression, are poly(ADP-ribosyl)ation (PAR) dependent and accompanied by an increase in nuclear PARP-1 and Poly(ADP) ribose molecules (pADPr) after forskolin stimulation. The upregulation of PARP-1 and pADPr is regulated by Protein kinase A (PKA) and extracellular signal-regulated kinase (ERK)--two kinases strongly associated with long-term plasticity and learning and memory. Selective inhibition of RNA Polymerase I (Pol I), responsible for the synthesis of precursor rRNA, results in the segmentation of nucleoli, the exclusion of PARP-1 from functional nucleolar compartments and disrupted L-LTP maintenance. Taken as a whole, these results suggest that new rRNAs (28S, 18S, and 5.8S ribosomal components)--hence, new ribosomes and nucleoli integrity--are required for the maintenance of long-term synaptic plasticity. This provides a mechanistic link between stimulation-dependent gene expression and the new protein synthesis known to be required for memory consolidation.
| S-EPMC4121280 | biostudies-literature
Project description:Cysteine string protein ? (CSP?) is a vesicle protein located in the presynaptic terminal of most synapses. CSP? is an essential molecular co-chaperone that facilitates the correct folding of proteins and the assembly of the exocytic machinery. The absence of this protein leads to altered neurotransmitter release and neurodegeneration in multiple model systems, from flies to mice. In humans, CSP? mutations are associated with the development of neuronal ceroid lipofuscinosis (NCL), a neurodegenerative disease characterized by intracellular accumulation of lysosomal material. Here, we review the physiological role of CSP? and the pathology resulting from the homozygous deletion of the gene or its mutations. In addition, we investigate whether long-term moderate reduction of the protein produces motor dysfunction. We found that 1-year-old CSP? heterozygous mice display a reduced ability to sustain motor unit recruitment during repetitive stimulation, which indicates that physiological levels of CSP? are required for normal neuromuscular responses in mice and, likely, in humans.
| S-EPMC5301022 | biostudies-literature
Project description:Long-term memory (LTM) formation has been linked with functional strengthening of existing synapses and other processes including de novo synaptogenesis. However, it is unclear whether synaptogenesis can contribute to LTM formation. Here, using ?-calcium/calmodulin kinase II autophosphorylation-deficient (T286A) mutants, we demonstrate that when functional strengthening is severely impaired, contextual LTM formation is linked with training-induced PSD95 up-regulation followed by persistent generation of multiinnervated spines, a type of synapse that is characterized by several presynaptic terminals contacting the same postsynaptic spine. Both PSD95 up-regulation and contextual LTM formation in T286A mutants required signaling by the mammalian target of rapamycin (mTOR). Furthermore, we show that contextual LTM resists destabilization in T286A mutants, indicating that LTM is less flexible when synaptic strengthening is impaired. Taken together, we suggest that activation of mTOR signaling, followed by overexpression of PSD95 protein and synaptogenesis, contributes to formation of invariant LTM when functional strengthening is impaired.
| S-EPMC3215030 | biostudies-literature
Project description:Memory storage in the brain relies on mechanisms acting on time scales from minutes, for long-term synaptic potentiation, to days, for memory consolidation. During such processes, neural circuits distinguish synapses relevant for forming a long-term storage, which are consolidated, from synapses of short-term storage, which fade. How time scale integration and synaptic differentiation is simultaneously achieved remains unclear. Here we show that synaptic scaling - a slow process usually associated with the maintenance of activity homeostasis - combined with synaptic plasticity may simultaneously achieve both, thereby providing a natural separation of short- from long-term storage. The interaction between plasticity and scaling provides also an explanation for an established paradox where memory consolidation critically depends on the exact order of learning and recall. These results indicate that scaling may be fundamental for stabilizing memories, providing a dynamic link between early and late memory formation processes.
| S-EPMC3814677 | biostudies-literature
Project description:Protein synthesis-dependent, late long-term potentiation (LTP) and depression (LTD) at glutamatergic hippocampal synapses are well characterized examples of long-term synaptic plasticity. Persistent increased activity of protein kinase M ζ (PKMζ) is thought essential for maintaining LTP. Additional spatial and temporal features that govern LTP and LTD induction are embodied in the synaptic tagging and capture (STC) and cross capture hypotheses. Only synapses that have been "tagged" by a stimulus sufficient for LTP and learning can "capture" PKMζ. A model was developed to simulate the dynamics of key molecules required for LTP and LTD. The model concisely represents relationships between tagging, capture, LTD, and LTP maintenance. The model successfully simulated LTP maintained by persistent synaptic PKMζ, STC, LTD, and cross capture, and makes testable predictions concerning the dynamics of PKMζ. The maintenance of LTP, and consequently of at least some forms of long-term memory, is predicted to require continual positive feedback in which PKMζ enhances its own synthesis only at potentiated synapses. This feedback underlies bistability in the activity of PKMζ. Second, cross capture requires the induction of LTD to induce dendritic PKMζ synthesis, although this may require tagging of a nearby synapse for LTP. The model also simulates the effects of PKMζ inhibition, and makes additional predictions for the dynamics of CaM kinases. Experiments testing the above predictions would significantly advance the understanding of memory maintenance.
| S-EPMC3410876 | biostudies-literature
Project description:Ca(2+)/calmodulin (CaM)-dependent protein kinase II (CaMKII) "autonomy" (T286-autophosphorylation-induced Ca(2+)-independent activity) is required for long-term potentiation (LTP) and for learning and memory, as demonstrated by CaMKII T286A mutant mice. The >20-year-old hypothesis that CaMKII stimulation is required for LTP induction, while CaMKII autonomy is required for LTP maintenance was recently supported using the cell-penetrating fusion-peptide inhibitor antCN27. However, we demonstrate here that ant/penetratin fusion to CN27 compromised CaMKII-selectivity, by enhancing a previously unnoticed direct binding of CaM to ant/penetratin. In contrast to antCN27, the improved cell-penetrating inhibitor tatCN21 (5 mum) showed neither CaM binding nor inhibition of basal synaptic transmission. In vitro, tatCN21 inhibited stimulated and autonomous CaMKII activity with equal potency. In rat hippocampal slices, tatCN21 inhibited LTP induction, but not LTP maintenance. Correspondingly, tatCN21 also inhibited learning, but not memory storage or retrieval in a mouse in vivo model. Thus, CaMKII autonomy provides a short-term molecular memory that is important in the signal computation leading to memory formation, but is not required as long-term memory store.
| S-EPMC2891520 | biostudies-literature
Project description:Utilizing a single nuclei multiomics approach, this study elucidates how enhancing histone lysine crotonylation regulates cell type specific gene expression and chromatin accessibility during memory consolidation.
2024-11-13 | GSE281007 | GEO
Project description:Executive functions of the brain are believed to require tonic dopamine inputs to the prefrontal cortex (PFC). It is unclear, however, how this background dopamine activity controls synaptic plasticity in the PFC, a possible underlying mechanism of executive functions. Using PFC slices, we show that pairing of dopamine with weak tetanic stimulation, a maneuver that otherwise induces NMDA receptor-independent long-term depression (LTD), induces long-term potentiation (LTP) when "primed" with dopamine. This "priming" occurs through the combined activation of D1 and D2 receptors and requires 12-40 min to develop. Moreover, concurrent synaptic activation of NMDA receptors during priming is necessary for this novel form of LTP. We suggest that a role of background dopamine signals in the PFC is to prevent high-frequency synaptic inputs from abnormally inducing LTD and to secure the induction of LTP.
| S-EPMC6674173 | biostudies-literature