Does the creation of memory involve mRNAs crossing the synaptic gap?

Does the creation of memory involve mRNAs crossing the synaptic gap?

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There is a diagram from a book titled "Teaching with the brain in mind". The diagram shows

The diagram appears to show that the "creation of memory" involves "messages coded by RNA" moving through an axon and being released into the synaptic gap, whereupon they presumably bind to the receptors on the other side of the synapse.

Unfortunately the book does not seem to provide any sources for this and I have not been able to find any sources corroborating this claim. Can anyone provide any references?

I have never heard of this pathway. Memory is usually assoiciated with synaptic plasticity by 'Long-term potentiation' (LTP), which has glutamate as a neurotransmitter. Neuroscience Exploring the brain (Bear, et al,. 2007), has a pretty good explanation of this process, if you're interrested. Motor patterns have more mechanisms than LTP, and are not as well understood.

Neurons have been shown to secrete exosomes (extracellular vesicles containing RNA) which may regulate neighbouring cells. However, this is mechanistically different from synaptic signalling by neurotransmitters. Moreover, I am not sure if exosome secretion is linked with synaptic activity and whether it plays a role in memory formation. Even if exosomal RNAs do have a role, their contribution is likely to be minor, compared to other pathways (such as NMDAR, mGluR, neuropeptides etc) involved in memory formation.


  • Bahrini, Insaf, et al. "Neuronal exosomes facilitate synaptic pruning by up-regulating complement factors in microglia." Scientific reports 5 (2015).
  • Bellingham, Shayne A., Bradley M. Coleman, and Andrew F. Hill. "Small RNA deep sequencing reveals a distinct miRNA signature released in exosomes from prion-infected neuronal cells." Nucleic acids research (2012): gks832.
  • Chivet, Mathilde, et al. "Emerging role of neuronal exosomes in the central nervous system." Front. Physiol. 3 (2012): 145.

Synaptic tagging

Synaptic tagging, or the synaptic tagging hypothesis, was first proposed in 1997 by Uwe Frey and Richard G. Morris it seeks to explain how neural signaling at a particular synapse creates a target for subsequent plasticity-related product (PRP) trafficking essential for sustained LTP and LTD. Although the molecular identity of the tags remains unknown, it has been established that they form as a result of high or low frequency stimulation, interact with incoming PRPs, and have a limited lifespan. [1]

Further investigations have suggested that plasticity-related products include mRNA and proteins from both the soma and dendritic shaft that must be captured by molecules within the dendritic spine to achieve persistent LTP and LTD. This idea was articulated in the synaptic tag-and-capture hypothesis. Overall, synaptic tagging elaborates on the molecular underpinnings of how L-LTP is generated and leads to memory formation.

REVIEW article

  • Institute of Molecular Biology and Biotechnology (IMBB), Foundation for Research and Technology Hellas (FORTH), Heraklion, Greece

In the study of memory engrams, synaptic memory allocation is a newly emerged theme that focuses on how specific synapses are engaged in the storage of a given memory. Cumulating evidence from imaging and molecular experiments indicates that the recruitment of synapses that participate in the encoding and expression of memory is neither random nor uniform. A hallmark observation is the emergence of groups of synapses that share similar response properties and/or similar input properties and are located within a stretch of a dendritic branch. This grouping of synapses has been termed “synapse clustering” and has been shown to emerge in many different memory-related paradigms, as well as in in vitro studies. The clustering of synapses may emerge from synapses receiving similar input, or via many processes which allow for cross-talk between nearby synapses within a dendritic branch, leading to cooperative plasticity. Clustered synapses can act in concert to maximally exploit the nonlinear integration potential of the dendritic branches in which they reside. Their main contribution is to facilitate the induction of dendritic spikes and dendritic plateau potentials, which provide advanced computational and memory-related capabilities to dendrites and single neurons. This review focuses on recent evidence which investigates the role of synapse clustering in dendritic integration, sensory perception, learning, and memory as well as brain dysfunction. We also discuss recent theoretical work which explores the computational advantages provided by synapse clustering, leading to novel and revised theories of memory. As an eminent phenomenon during memory allocation, synapse clustering both shapes memory engrams and is also shaped by the parallel plasticity mechanisms upon which it relies.


The synaptic tagging and capture hypothesis of protein synthesis-dependent long-term potentiation asserts that the induction of synaptic potentiation creates only the potential for a lasting change in synaptic efficacy, but not the commitment to such a change. Other neural activity, before or after induction, can also determine whether persistent change occurs. Recent findings, leading us to revise the original hypothesis, indicate that the induction of a local, synapse-specific 'tagged' state and the expression of long-term potentiation are dissociable. Additional observations suggest that there are major differences in the mechanisms of functional and structural plasticity. These advances call for a revised theory that incorporates the specific molecular and structural processes involved. Addressing the physiological relevance of previous in vitro findings, new behavioural studies have experimentally translated the hypothesis to learning and the consolidation of newly formed memories.


We are grateful to Patrick Spooner for technical assistance with the event arena and Jacqueline Friel for assistance with behavioural training of mice.

Funding statement

This work was supported by a European Research Council Advanced Investigator Grant to R.G.M.M. and Guillén Fernández (NEUROSCHEMA, no. 268800 ). T.T. was supported by the Mitsubishi Tanabe Pharma Corporation and the UK Medical Research Council , to whom we are also grateful for past funding to R.G.M.M. and for a studentship and in vivo skills award currently held by A.J.D.

UPF2 leads to degradation of dendritically targeted mRNAs to regulate synaptic plasticity and cognitive function

Synaptic plasticity requires a tight control of mRNA levels in dendrites. RNA translation and degradation pathways have been recently linked to neurodevelopmental and neuropsychiatric diseases, suggesting a role for RNA regulation in synaptic plasticity and cognition. While the local translation of specific mRNAs has been implicated in synaptic plasticity, the tightly controlled mechanisms that regulate local quantity of specific mRNAs remain poorly understood. Despite being the only RNA regulatory pathway that is associated with multiple mental illnesses, the nonsense-mediated mRNA decay (NMD) pathway presents an unexplored regulatory mechanism for synaptic function and plasticity. Here, we show that neuron-specific disruption of UPF2, an NMD component, in adulthood attenuates learning, memory, spine density, synaptic plasticity (L-LTP), and potentiates perseverative/repetitive behavior in mice. We report that the NMD pathway operates within dendrites to regulate Glutamate Receptor 1 (GLUR1) surface levels. Specifically, UPF2 modulates the internalization of GLUR1 and promotes its local synthesis in dendrites. We identified neuronal Prkag3 mRNA as a mechanistic substrate for NMD that contributes to the UPF2-mediated regulation of GLUR1 by limiting total GLUR1 levels. These data establish that UPF2 regulates synaptic plasticity, cognition, and local protein synthesis in dendrites, providing fundamental insight into the neuron-specific function of NMD within the brain.

Does the creation of memory involve mRNAs crossing the synaptic gap? - Biology

Memory and synaptic plasticity exhibit distinct temporal phases, with long-lasting forms distinguished by their dependence on macromolecular synthesis. Prevailing models for the molecular mechanisms underlying long-lasting synaptic plasticity have largely focused on transcriptional regulation. However, a growing body of evidence now supports a crucial role for neuronal activity-dependent mRNA translation, which may occur in dendrites for a subset of neuronal mRNAs. Recent work has begun to define the signaling mechanisms coupling synaptic activation to the protein synthesis machinery. The ERK and mTOR signaling pathways have been shown to regulate the activity of the general translational machinery, while the translation of particular classes of mRNAs is additionally controlled by gene-specific mechanisms. Rapid enhancement of the synthesis of a diverse array of neuronal proteins through such mechanisms provides the components necessary for persistent forms of LTP and LTD. These findings have important implications for the synapse specificity and associativity of protein synthesis-dependent changes in synaptic strength.


Dysregulation of the signaling pathways that engage protein synthesis have been linked to the pathophysiology of several neurodegenerative diseases and neurodevelopmental disorders (Bagni et al. 2012, Darnell & Klann 2013, Swanger & Bassell 2011). Indeed, disease progression in Alzheimer’s disease (AD) and other neurodegenerative disorders has recently been linked to dysregulation of eIF2α-mediated translational control, whereas several components of the mTORC1 signaling pathway are implicated in the etiology of syndromic ASDs. Finally, loss-of-function mutations in the RNA binding protein and putative translational repressor FMRP cause FXS.

Translational Dysregulation in Neurodegenerative Diseases

Suppression of polysomal mRNA translation in the brains of AD patients was first documented more than 20 years ago (Langstrom et al. 1989). A prevailing hypothesis postulates that the deficits in translational control in AD could be due to aberrant eIF2α phosphorylation. Consistent with this hypothesis, increased phosphorylation of eIF2α has been observed in postmortem analysis of AD patients’ brains (Chang et al. 2002a, b Page et al. 2006) and also in numerous experimental preparations, including cultured neurons treated with synthetic Aβ peptides (Chang et al. 2002a) and brain sections of AD mouse models (Ma et al. 2013, O𠆜onnor et al. 2008, Page et al. 2006). The eIF2α kinases PKR and PERK are activated under similar conditions (Chang et al. 2002a, b O𠆜onnor et al. 2008 Onuki et al. 2004 Page et al. 2006). As general translation is depressed, translation of ATF4 and β-secretase (BACE1) mRNAs, both of which contain uORFs in the 5′ UTR, appear to be elevated by p-eIF2α in AD brains (O𠆜onnor et al. 2008). Because BACE1 promotes amyloidogenesis by initiating cleavage of amyloid precursor protein (APP) to form Aβ, investigators believe that dysregulated translation in AD, via elevated p-eIF2α, establishes a feedforward loop that progressively diminishes the overall structure and function of the affected neuronal population.

Significant efforts have been directed toward restoring physiological translational control in AD in hopes of hindering disease progression. In a recent study, deletion of PERK or GCN2 in APP/PS1 mice (APPswe, PSEN1dE9) not only corrected p-eIF2α levels and the depression in global translation but also rescued the deficits in synaptic plasticity and spatial memory displayed at 10� months (Ma et al. 2013). In contrast, however, genetic deletion of GCN2 in the 5XFAD (five familiar AD mutations) mouse model, in which AD progresses faster than in APP/PS1 mice, did not rescue but instead aggravated the memory deficits (Devi & Ohno 2013). Thus, whether blockade of eIF2α kinases could be an effective treatment for AD remains unclear (however, see discussion below).

PKR-eIF2α signaling is also implicated in AD (Morel et al. 2009). PKR activity is upregulated in AD patients’ brains and in mouse models of AD (Chang et al. 2002b). In primary neurons, both genetic deletion and pharmacological inhibition of PKR prevented inflammation and apoptosis induced by Aβ peptides (Chang et al. 2002a Couturier et al. 2010, 2011). Given that genetic or pharmacological inhibition of PKR enhances learning and memory in mice (Zhu et al. 2011), PKR is a promising target for AD treatment. In this regard, a recent study found that exposure of neuronal cultures to β-amyloid oligomers (AβOs) triggered PKR, but not PERK (Laurenco et al. 2013), a process that is attenuated by PKRi. Furthermore, intracerebroventricular infusion of AβOs increased eIF2α phosphorylation and resulted in cognitive impairment only in wild-type mice but not in mice lacking PKR. Hence, in future studies, it would be interesting to determine if direct inhibition of eIF2α, by other means, could also restore the memory deficits in AD mouse models.

MTORC1 Translational Control in Autism Spectrum Disorders

ASDs are a group of neurodevelopmental disorders that share common symptoms, including impaired social interactions, abnormal repetitive behavior, and often intellectual disability (Fombonne 1999, Mefford et al. 2012). Although they are genetically heterogeneous, ASDs are heritable, and some forms are linked to single gene mutations (Zoghbi & Bear 2012). In this regard, human mutations in negative regulators of mTORC1, such as PTEN or tuberous sclerosis complex (TSC) proteins (TSC1/2), are associated with ASD (O’Roak et al. 2012, Sahin 2012). Moreover, mice with mutations in Pten or Tsc1/2 causing hyperactivation of mTORC1, exhibit behaviors analogous to those of human ASD patients (see Costa-Mattioli & Monteggia 2013). Remarkably, the ASD-like phenotypes in mouse models with elevated mTORC1 signaling can be arrested or even reversed by applying rapamycin and/or its synthetic derivatives (termed rapalogs). Thus, considerable recent attention has been directed toward establishing a mechanistic understanding of how the mTORC1 signaling pathway regulates synaptic plasticity and the development of novel, mechanism-based therapies to treat mTORC1-related ASDs.

mTOR consists of two distinct complexes, mTORC1 and mTORC2, each of which critically contributes to synaptic plasticity (Stoica et al. 2011, Huang et al. 2013). Although mTORC2 activity could control some of the ASD-like behaviors in models of mTORC1 hyperactivity, here we focus on what is known about dysregulation of the mTORC1 signaling pathway in relation to disorders of synaptic dysfunction.

mTORC1 integrates a diverse set of extracellular and intracellular inputs to manage cell growth and metabolism, among other essential functions in most mammalian cell types (Laplante & Sabatini 2012). Neurons further exploit the mTORC1 pathway for the integration of activity-dependent signaling. Extracellular neurotrophin or glutamate binding to transmembrane receptors activates the PI3K-Akt-mTORC1 signaling pathway, which is outlined in Figure 2b .

Heterozygous loss-of-function mutations in either the TSC1 or TSC2 genes cause TSC, a disease that presents with neurological deficits including ASD, epilepsy, and intellectual disability in

20�% of patients (Fombonne 1999, Mefford et al. 2012). Like TSC patients, mice heterozygous for either Tsc1 or Tsc2 show deficits in several cognitive tasks including spatial learning in the Morris water maze, context discrimination, and fear-conditioning paradigms (Ehninger et al. 2008, Goorden et al. 2007). Tsc1 +/− mice are also abnormal in their social behavior (Goorden et al. 2007). In addition, spine density and AMPA/NMDA ratios are increased in Tsc1 +/− mutants while stimuli that typically induce E-LTP produce L-LTP in Tsc2 +/− mutants. mGluR-LTD is also impaired in Tsc1- and Tsc2-deficient neurons (Auerbach et al. 2011, Bateup et al. 2011). At the network level, genetic deletion of Tsc1 results in chronic hyperactivity owing to a loss of inhibitory synaptic transmission (Bateup et al. 2013). These behavioral and synaptic phenotypes are thought to be caused by the hyperactivation of mTORC1 because they are restored by rapamycin.

Inherited mutations in PTEN, which also increase mTORC1 activity, commonly result in multiple neurological phenotypes including ASD, intellectual disability, and macrocephaly in humans (Endersby & Baker 2008). Similarly, conditional knockout of Pten in the mouse brain causes impairments in social interaction and learning as well as epilepsy and exaggerated neuronal arborization leading to macrocephaly (Kwon et al. 2006). As in the case of Tsc2 +/− mice (Bateup et al. 2013), bidirectional plasticity (LTP and LTD) is altered in Pten-deficient mice. Analysis of Nse-Cre Pten conditional knockout mice revealed that the alterations in synaptic plasticity appear prior to the onset of morphological defects and behavioral abnormalities (Takeuchi et al. 2013). Thus, synaptic dysfunction associated with mTORC1 upregulation could be causally related to both the morphological and the cognitive deficits observed in human patients with loss-of-function mutations in PTEN.

Consistent with a causal role for mTORC1 upregulation in the etiology of ASD-like phenotypes in TSC and/or PTEN-ASD mouse models, rapamycin or rapalog treatment reverses many of the synaptic and behavioral phenotypes in these models (Costa-Mattioli & Monteggia 2013, Ehninger & Silva 2011). The exact mechanisms by which rapamycin ameliorates cognitive dysfunction phenotypes remain unclear as mTORC1 regulates not only translation rates, but also lipid synthesis, autophagy, and mitochondrial function.

The most likely mechanism by which excessive mTORC1 signaling could cause ASD phenotypes is by upregulating cap-dependent translation because hyperactivation of mTORC1 promotes eIF4F complex formation (Gingras et al. 2004). Like mutant mice with hyperactive mTORC1 signaling, mice with elevated eIF4F complex in the brain (4E-BP2 knockout mice or transgenic mice overexpressing eIF4E) also show ASD-like phenotypes, including deficits in social behaviors and stereotypic repetitive behaviors (Gkogkas et al. 2013, Santini et al. 2013). Moreover, disruption of eIF4F complex formation with the protein synthesis inhibitor 4EGI-1 fully rescues the neurophysiological and autistic-like behavioral deficits in both the eIF4E-transgenic mice and the 4E-BP2 knockout mice.

Given that eIF4F complex formation is presumably elevated in TSC and PTEN-ASD mouse models, one would predict that 4EGI-1 treatment could rescue the plasticity and behavioral phenotypes in these models. Conversely, mice overexpressing eIF4E, but not 4E-BP2 knockout mice, should be sensitive to rapamycin-mediated mTORC1 inhibition. These experiments would significantly bolster the notion that the primary mechanism by which mTORC1 regulates synaptic plasticity is through eIF4F-mediated translational control. In addition, whether elevated eIF4F complex formation in the ASD brain leads to an increase in global or specific protein synthesis remains unresolved. In mice overexpressing eIF4E general translation is increased (Santini et al. 2013), whereas in 4E-BP2 knockout mice the translation of specific mRNAs encoding the ASD-associated synaptic adhesion proteins neuroligins 1𠄴 (Nlgn1𠄴) is upregulated (Gkogkas et al. 2013). As discussed above, whether, and if so how, the mRNA features that dictate mTORC1-mediated regulation of the synthesis of these synaptic proteins differ from those in nonneuronal cells are important questions that have yet to be thoroughly addressed.

Translational Control in Fragile X Syndrome

Dysregulation of translation is also implicated in the pathophysiology of FXS, the most common inherited cause of intellectual disability and ASD (for review see Bassell & Warren 2008, Bhakar et al. 2012, Darnell & Klann 2013, Nelson et al. 2013). FXS is caused by transcriptional silencing of the Fmr1 gene due to CGG triplet repeat expansion in the 5′ UTR of the mRNA (Bassell & Warren 2008, Nelson et al. 2013). Fmr1 encodes FMRP, an mRNA binding protein that represses translation (Laggerbauer et al. 2001, Li et al. 2001). Accordingly, deletion of Fmr1 leads to a region-specific increase in general translation (Qin et al. 2005). In addition, protein synthesis inhibitors rescue the LTM phenotype in Drosophila FXS mutants (Bolduc et al. 2008). The use of an in vivo UV-crosslinking procedure (CLIP) combined with high throughput sequencing (CLIP-seq) of polysome-associated FMRP showed that FMRP binds to a specific subset of mRNAs. The targets of FMRP include several mRNAs that encode proteins with significant roles in synaptic function, such as NMDAR and mGluR subunits, but also include ASD-linked mRNAs such as Pten, Tsc2, and other members of the mTOR signaling pathway (Darnell et al. 2011). In this regard, mTORC1 activity seems to be upregulated in subjects (Hoeffer et al. 2012) and mouse models of FXS (Sharma et al. 2010). Some of the phenotypes observed in Fmr1 knockout mice are restored by rapalog treatment (Busquets-Garcia et al. 2013). In addition, genetic removal of S6K1 also corrects some of the phenotypes in FXS mice (Bhattacharya et al. 2012). How S6K1 regulates translation of FMRP-target mRNAs is unclear. Given that, in one model, FMRP represses translation once associated with polysomes (Khandjian et al. 1996, Stefani et al. 2004), an interesting possibility is that S6K-mediated phosphorylation of eEF2 derepresses translation elongation.

Because eIF4F complex formation seems to be increased in the FXS mouse model (Sharma et al. 2010), FMRP could also repress translation at the initiation level. In this model, FMRP binds to its partner CYFIP1, which acts as a 4E-BP, binding eIF4E through a noncanonical eIF4E motif, thus repressing cap-dependent translation initiation (Napoli et al. 2008).

Several important questions remain regarding the role of translational control in FXS pathophysiology. First, does FMRP inhibit polypeptide elongation or translation initiation? If so, is this a dynamic and reversible process? Second, does disruption of eIF4F complex formation rescue some of the FXS phenotypes? Indeed, would this be specific to eIF4F, or could a more general translation inhibitor, like in FXS Drosophila experiments (Bolduc et al. 2008), also correct the FXS phenotypes in mice and/or humans? In this regard, crossing Tsc2 mice—which are expected to have increased eIF4F but show reduced overall translation rates and several behavioral deficits similar to the Fmr1 knockout mice—with Fmr1 knockout mice rescued the mutant phenotypes (Auerbach et al. 2011). Third, if FMRP binds to specific mRNAs, why is general translation increased in Fmr1 knockout hippocampus? Furthermore, given that modulation of actin polymerization through PAK also corrects the behavioral deficits in the FXS mouse (Dolan et al. 2013, Hayashi et al. 2004), it will be interesting to determine the link between translation and cytoskeletal dynamics in FXS. Recent data demonstrating that, through interaction with Rac1, CYFIP1 also contributes to cytoskeletal remodeling at dendritic spines represent a promising first step in this direction (De Rubeis et al. 2013).

Summary and Conclusions

Trettenbrein’s (2016) critiques of the synaptic theory of memory can be answered by the published evidence for the synaptic theory of memory, as argued in this article. The synaptic theory of memory remains the most empirically plausible explanation for the neurobiological basis of memory, even if it may need modification (Jirenhed et al., 2017). In this article we have addressed the six critiques raised by Trettenbrein (2016) and through the use of recent neurophysiologic literature, we have demonstrated that synaptic change is only the first step in formation of the cell assemblies and phase sequences postulated by Hebb (1949), which together constitute the Hebbian account of memory. We have shown how the concepts of synaptic change and the cell assembly are used to understand the neuroanatomical, cellular, molecular and genetic bases of memory and of neurological disorders. We have also shown how neuroimaging studies, computer modeling and robotics have used the Hebbian learning rules and cell assemblies to develop computer learning and “intelligent” robots. Our critique of Trettenbrein (2016) has focused on the term �mise” (death, downfall, disappearance or final fate) of the synaptic theory of memory. We believe that the synaptic theory of memory has not died, but has gone from strength to strength. But there are two components of this theory: synaptic plasticity and intra-cellular biochemical changes. At issue is whether “memory” consists of the synaptic changes activated by intracellular biochemical changes OR whether memory consists of the intracellular biochemical changes expressed via synaptic plasticity. Our argument is that memory, as conceived by Hebb, consists of both synaptic plasticity and “intrinsic plasticity” of the neurons (Sehgal et al., 2013 Titley et al., 2017 Lisman et al., 2018). You cannot separate one from the other.


As a result of tremendous progress during the past 15 years, studies have led to the conclusion that the activation of patterns of gene expression organized in cascades, whereby transcription factors regulate the expression of regulatory immediate early genes, underlies long-term synaptic plasticity and long-term memory formation. Families of transcription factors involved include the CREB, C/EBP, Rel, AP-1, and NFκB families, suggesting that after learning, information is transformed into long-term memory by inducing “different” cell states. Both transcription activators and repressors are recruited, and long-term changes are accompanied by modifications of chromatin and DNA at genes known to be critically involved in long-term memory. Future investigations will aim to identify the patterns of target genes, the expression regulation of which, over time, mediates long-term memory formation, as well as to elucidate the temporal dynamics of the gene regulation processes.


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