Activity-dependent remodeling of genome architecture in engram cells facilitates memory formation and recall

Abstract DNA methylation is a crucial epigenetic mark for activity-dependent gene expression in neurons. Very little is known about how synaptic signals impact promoter methylation in neuronal nuclei. In this study we show that protein levels of the principal de novo DNA-methyltransferase in neurons, DNMT3A1, are tightly controlled by activation of N-methyl-D-aspartate receptors (NMDAR) containing the GluN2A subunit. Interestingly, synaptic NMDARs drive degradation of the methyltransferase in a neddylation-dependent manner. Inhibition of neddylation, the conjugation of the small ubiquitin-like protein NEDD8 to lysine residues, interrupts degradation of DNMT3A1. This results in deficits in promoter methylation of activity-dependent genes, as well as synaptic plasticity and memory formation. In turn, the underlying molecular pathway is triggered by the induction of synaptic plasticity and in response to object location learning. Collectively, the data show that plasticity-relevant signals from GluN2A-containing NMDARs control activity-dependent DNA-methylation involved in memory formation.

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Synaptic control of DNA-methylation involves activity-dependent degradation of DNMT3a1 in the nucleus

10.1101/602151 ◽

2019 ◽

Cited By ~ 1

Author(s):

Gonca Bayraktar ◽

PingAn Yuanxiang ◽

Guilherme M Gomes ◽

Aessandro D Confettura ◽

Syed A Raza ◽

...

Keyword(s):

Dna Methylation ◽

Synaptic Plasticity ◽

Promoter Methylation ◽

Dna Methyltransferase ◽

De Novo ◽

Memory Formation ◽

Epigenetic Mark ◽

Dependent Manner ◽

Synaptic Control ◽

Activity Dependent

AbstractDNA-methylation is a crucial epigenetic mark for activity-dependent gene expression in neurons. Very little is known how synaptic signals impact promoter methylation in neuronal nuclei. In this study we show that protein levels of the principal de novo DNA-methyltransferase in neurons, DNMT3a1, are tightly controlled by activation of N-methyl-D-aspartate receptors (NMDAR) containing the GluN2A subunit. Interestingly, synaptic NMDAR drive degradation of the methyltransferase in a neddylation-dependent manner. Inhibition of neddylation, the conjugation of the small ubiquitin-like protein NEDD8 to lysine residues, interrupts degradation of DNMT3a1 and results in deficits of promoter methylation of activity-dependent genes, synaptic plasticity as well as memory formation. In turn, the underlying molecular pathway is triggered by the induction of synaptic plasticity and in response to object location learning. Collectively the data show that GluN2A containing NMDAR control synapse-to-nucleus signaling that links plasticity-relevant signals to activity-dependent DNA-methylation involved in memory formation.

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The synaptic plasticity and memory hypothesis: encoding, storage and persistence

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2013.0288 ◽

2014 ◽

Vol 369 (1633) ◽

pp. 20130288 ◽

Cited By ~ 243

Author(s):

Tomonori Takeuchi ◽

Adrian J. Duszkiewicz ◽

Richard G. M. Morris

Keyword(s):

Synaptic Plasticity ◽

Optical Imaging ◽

Brain Area ◽

Molecular Genetic ◽

Memory Formation ◽

New Work ◽

Necessary And Sufficient ◽

Activity Dependent ◽

The Brain

The synaptic plasticity and memory hypothesis asserts that activity-dependent synaptic plasticity is induced at appropriate synapses during memory formation and is both necessary and sufficient for the encoding and trace storage of the type of memory mediated by the brain area in which it is observed. Criteria for establishing the necessity and sufficiency of such plasticity in mediating trace storage have been identified and are here reviewed in relation to new work using some of the diverse techniques of contemporary neuroscience. Evidence derived using optical imaging, molecular-genetic and optogenetic techniques in conjunction with appropriate behavioural analyses continues to offer support for the idea that changing the strength of connections between neurons is one of the major mechanisms by which engrams are stored in the brain.

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Rapid, experience-dependent translation of neurogranin enables memory encoding

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1716750115 ◽

2018 ◽

Vol 115 (25) ◽

pp. E5805-E5814 ◽

Cited By ~ 17

Author(s):

Kendrick J. Jones ◽

Sebastian Templet ◽

Khaled Zemoura ◽

Bozena Kuzniewska ◽

Franciso X. Pena ◽

...

Keyword(s):

Protein Synthesis ◽

De Novo ◽

Fragile X ◽

Memory Formation ◽

Long Term Memory ◽

Memory Encoding ◽

Contextual Memory ◽

Protein Levels ◽

Mrna Pool ◽

Activity Dependent

Experience induces de novo protein synthesis in the brain and protein synthesis is required for long-term memory. It is important to define the critical temporal window of protein synthesis and identify newly synthesized proteins required for memory formation. Using a behavioral paradigm that temporally separates the contextual exposure from the association with fear, we found that protein synthesis during the transient window of context exposure is required for contextual memory formation. Among an array of putative activity-dependent translational neuronal targets tested, we identified one candidate, a schizophrenia-associated candidate mRNA, neurogranin (Ng, encoded by the Nrgn gene) responding to novel-context exposure. The Ng mRNA was recruited to the actively translating mRNA pool upon novel-context exposure, and its protein levels were rapidly increased in the hippocampus. By specifically blocking activity-dependent translation of Ng using virus-mediated molecular perturbation, we show that experience-dependent translation of Ng in the hippocampus is required for contextual memory formation. We further interrogated the molecular mechanism underlying the experience-dependent translation of Ng, and found that fragile-X mental retardation protein (FMRP) interacts with the 3′UTR of the Nrgn mRNA and is required for activity-dependent translation of Ng in the synaptic compartment and contextual memory formation. Our results reveal that FMRP-mediated, experience-dependent, rapid enhancement of Ng translation in the hippocampus during the memory acquisition enables durable context memory encoding.

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Causal explanation of individual differences in human sensorimotor memory formation

10.1101/255091 ◽

2018 ◽

Cited By ~ 2

Author(s):

Pierre Petitet ◽

Jill X. O’Reilly ◽

Ana M. Gonçalves ◽

Piergiorgio Salvan ◽

Shigeru Kitazawa ◽

...

Keyword(s):

Sensorimotor Cortex ◽

Causal Explanation ◽

Mechanistic Explanation ◽

Memory Formation ◽

Cognitive State ◽

Dependent Effect ◽

State Dependent ◽

Sensorimotor Memory ◽

Memory Persistence ◽

Activity Dependent

AbstractSensorimotor cortex mediates the formation of adaptation memory. Individuals differ in the rate at which they acquire, retain, and generalize adaptation. We present a mechanistic explanation of the neurochemical and computational causes of this variation in humans. Neuroimaging identified structural, functional and neurochemical covariates of a computational parameter that determines memory persistence. To establish causality, we increased sensorimotor cortex excitability during adaptation, using transcranial direct current stimulation. As predicted, this increased retention. Inter-individual variance in the stimulation-induced E:I increase predicted the computational change, which predicted the memory gain. These relations did not hold, and memory was unchanged, with stimulation applied before adaptation. This cognitive state dependent effect was modulated by the BDNF val66met genetic polymorphism. Memory was enhanced by stimulation in Val/Val carriers only, implicating a mechanistic role for activity-dependent BDNF secretion. Sensorimotor cortex E:I causally determines the time constant of memory persistence, explaining phenotypic variation in adaptation decay.

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Context memory formation requires activity-dependent protein degradation in the hippocampus

Learning & Memory ◽

10.1101/lm.045443.117 ◽

2017 ◽

Vol 24 (11) ◽

pp. 589-596 ◽

Cited By ~ 9

Author(s):

Patrick K. Cullen ◽

Nicole C. Ferrara ◽

Shane E. Pullins ◽

Fred J. Helmstetter

Keyword(s):

Protein Degradation ◽

Memory Formation ◽

Dependent Protein ◽

Activity Dependent ◽

Context Memory

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Malfunctional Reorganization in the Developing Limbo-Prefrontal System in Animals: Implications for Human Psychoses?

Zeitschrift für Neuropsychologie ◽

10.1024//1016-264x.12.1.8 ◽

2001 ◽

Vol 12 (1) ◽

pp. 8-14

Author(s):

Gertraud Teuchert-Noodt ◽

Ralf R. Dawirs

Keyword(s):

Prefrontal Cortex ◽

Mental Disorders ◽

Dentate Gyrus ◽

Cognitive Functions ◽

Experimental Approach ◽

Regulatory Mechanisms ◽

Hippocampal Dentate Gyrus ◽

Non Invasive ◽

Invasive Method ◽

Activity Dependent

Abstract: Neuroplasticity research in connection with mental disorders has recently bridged the gap between basic neurobiology and applied neuropsychology. A non-invasive method in the gerbil (Meriones unguiculus) - the restricted versus enriched breading and the systemically applied single methamphetamine dose - offers an experimental approach to investigate psychoses. Acts of intervening affirm an activity dependent malfunctional reorganization in the prefrontal cortex and in the hippocampal dentate gyrus and reveal the dopamine position as being critical for the disruption of interactions between the areas concerned. From the extent of plasticity effects the probability and risk of psycho-cognitive development may be derived. Advance may be expected from insights into regulatory mechanisms of neurogenesis in the hippocampal dentate gyrus which is obviously to meet the necessary requirements to promote psycho-cognitive functions/malfunctions via the limbo-prefrontal circuit.

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