A trace of silence: memory and microRNA at the synapse

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Identifying the neural circuits that mediate particular behaviors and uncovering their plasticity is an endeavor at the heart of neuroscience. This effort is allied with the elucidation of plasticity mechanisms, because the molecular determinants of plasticity can be markers for the neurons and synapses that are modified by experience. Of particular interest is protein synthesis localized to the synapse, which might establish and maintain the stable modification of neuronal properties, including the pattern and strength of synaptic connections. Recent studies reveal that microRNAs and the RISC pathway regulate synaptic protein synthesis. Is synaptic activity of the RISC pathway a molecular signature of memory?

Introduction

A fascinating area of current research seeks to uncover the neural circuits that underlie specific behaviors and determine how these circuits are modified by experience. Recent studies in the fly and worm suggest it should be possible to demarcate neural circuits underlying a plethora of behaviors [1]. As these circuits are resolved, one can begin to search for nodes of plasticity and to localize the long sought after ‘memory traces’ and ‘engrams’, the combined stable changes to circuit function that constitute a memory. Eventually, these stable changes might be charted by maps of experience-induced changes to the brain. A somewhat advanced example of this undertaking is the identification of short-term memory traces formed by the association of odor with electric shock in Drosophila melanogaster. Hallmarks of plasticity can be found at distinct nodes in the well-described Drosophila olfactory circuitry [2]. Additional recent examples include circuits that mediate the association of odor with pathogenic bacteria in C. elegans [3] and features of the visual field with aversive heat in Drosophila [4]. Allied with this delineation of circuit elements and their connectivity are advances in the molecular biology of memory. As the molecular signatures of engrams are identified, it becomes possible to map them onto circuits as an animal is conditioned and a memory is formed. In this review, we consider such advances and their implications for creating brain maps of memory.

We focus here on stable (or long-term) memory. Long-term memory (LTM) is presumed to reflect the stable modification of circuit properties, including the pattern and strength of synaptic connections. New gene expression, and hence mRNA and protein synthesis, is required for the formation of an LTM. Neural activity accompanying the induction of an LTM can trigger a biochemical cascade leading to the nucleus, where CREB (the cAMP response-element binding protein)-mediated transcription is presumed to contribute to changes in neuronal and circuit properties [5]. Another strategy for the modification of circuit behavior is the synaptic translation of selectively localized mRNAs [6, 7]. This spatially restricted form of translation enables proteins to be synthesized and possibly retained at specific synapses within a neuron, perhaps locally tied to the specific forms of synaptic activity that trigger plasticity [2]. Although attractive, this model for ‘subcellular’ events that might occur as a memory forms remains unproven. An alternative mechanism, in which nuclear and cytoplasmic activities are integrated, and proteins and/or mRNA are selectively captured at appropriately stimulated synapses, has also been considered [8]. This mechanism includes a role for a stable ‘synaptic tag’ as part of the synaptic capture mechanism. The identity of these putative tags and their mode of action in synaptic plasticity have been elusive [8].

Recent studies on LTM in the fruit fly, dendritic spine development in the mouse hippocampus and neurite sprouting from rat cortical neurons reveal an attractive and conserved mechanism of plasticity involving small endogenous RNAs, known as microRNAs (miRNAs), that are specifically expressed in the brains of several species [9••, 10••, 11•]. Do miRNAs play a role in a memory-related mechanism that regulates protein synthesis at selected synapses?

Section snippets

Regulated protein synthesis in the vicinity of the synapse

Several mechanisms have been identified that appear to regulate protein synthesis from mRNAs that are selectively localized to the vicinity of the synapse. These include an mRNA 3′UTR-dependent mechanism mediated by the RNA-binding proteins cytoplasmic polyadenylation element binding protein (CPEB) and cleavage and polyadenylation specificity factor (CPSF) [12]; an mRNA 5′ Cap-mediated rapamysin-sensitive mechanism [13]; and a mechanism that can utilize an mRNA internal ribosome entry site

Synaptic protein synthesis associated with memory is regulated by RISC in Drosophila

Long-term memory (LTM) has long been known to require protein synthesis, in Drosophila as in mammals [37]. However, protein synthesis had not been documented specifically at synapses in any animal forming a memory. Recently, however, Ashraf et al. [9••] reported that synaptic protein synthesis indeed occurred at sites in the Drosophila brain as a stable associative memory of odor paired with aversive electric shock is formed. This protein synthesis occurred in memory-specific patterns at the

Dendrite and neurite under miRNA control

On the basis of earlier identification of several brain-specific miRNAs in the mouse, Schratt et al. [10••] investigated a possible link between miRNAs and dendritic spine dynamics. Spines house dendritic postsynaptic sites; their dynamic formation or dissolution is considered a hallmark of synaptic plasticity. The microRNA miR134 was found localized at the base of hippocampal dendrites [10••]. A search for miR134 binding sites in mRNAs for genes regulated by the neurotrophin BDNF revealed one

Memory, RISC and CPEB

One would suppose that the CPEB and RISC pathways intersect in their control of synaptic translation; there is suggestive evidence to this effect (Figure 1a). The expression of several proteins is increased with the induction of a LTM in Drosophila, and these proteins are indeed required for LTM [22] and have miRNA binding sites in their 3′UTRs [9••, 40]. These include Orb (one of the two CPEBs in Drosophila), Staufen and Pumilio, proteins with well-documented roles in translational control and

Concluding thoughts

Remarkably, these recent studies reveal that regulation of synaptic protein synthesis by miRNAs and RISC might be a generally conserved mechanism. Yet much remains unclear. Although the role of RISC in memory has been directly demonstrated in Drosophila [9••], this has not been established in a mammalian system, despite the considerable evidence connecting dendritic spine dynamics and BDNF signaling to synaptic plasticity and memory [43]. An exciting possibility suggested by these studies is

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was supported by a Merck Fellowship (to SI Ashraf) and National Institute of Health grant EY10112 to S Kunes. We thank J Gray and B Zagaeski for comments on the manuscript.

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