Untangling the two-way signalling route from synapses to the nucleus, and from the nucleus back to the synapses.

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Untangling the two-way signalling route from synapses to the nucleus, and from the nucleus back to the synapses Mio Nonaka, Hajime Fujii, Ryang Kim, Takashi Kawashima, Hiroyuki Okuno and Haruhiko Bito Phil. Trans. R. Soc. B 2014 369, 20130150, published 2 December 2013

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Untangling the two-way signalling route from synapses to the nucleus, and from the nucleus back to the synapses rstb.royalsocietypublishing.org

Review Cite this article: Nonaka M, Fujii H, Kim R, Kawashima T, Okuno H, Bito H. 2014 Untangling the two-way signalling route from synapses to the nucleus, and from the nucleus back to the synapses. Phil. Trans. R. Soc. B 369: 20130150. http://dx.doi.org/10.1098/rstb.2013.0150 One contribution of 35 to a Discussion Meeting Issue ‘Synaptic plasticity in health and disease’. Subject Areas: neuroscience, molecular biology, cellular biology, biochemistry, behaviour Keywords: calcium, Arc, synaptic tag, CaMKII, CREB, memory trace Author for correspondence: Haruhiko Bito e-mail: [email protected]

†

These authors contributed equally to this study. ‡ Present address: Janalia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. § Present address: Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.

Mio Nonaka1,2,†, Hajime Fujii1,3,†, Ryang Kim1,3,†, Takashi Kawashima1,†,‡, Hiroyuki Okuno1,3,†,§ and Haruhiko Bito1,3 1 Department of Neurochemistry, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan 2 Centre for Cognitive and Neural Systems, University of Edinburgh, Edinburgh, UK 3 CREST-JST, Chiyoda-ku, Tokyo 102-0076, Japan

During learning and memory, it has been suggested that the coordinated electrical activity of hippocampal neurons translates information about the external environment into internal neuronal representations, which then are stored initially within the hippocampus and subsequently into other areas of the brain. A widely held hypothesis posits that synaptic plasticity is a key feature that critically modulates the triggering and the maintenance of such representations, some of which are thought to persist over time as traces or tags. However, the molecular and cell biological basis for these traces and tags has remained elusive. Here, we review recent findings that help clarify some of the molecular and cellular mechanisms critical for these events, by untangling a two-way signalling crosstalk route between the synapses and the neuronal soma. In particular, a detailed interrogation of the soma-to-synapse delivery of immediate early gene product Arc/ Arg3.1, whose induction is triggered by heightened synaptic activity in many brain areas, teases apart an unsuspected ‘inverse’ synaptic tagging mechanism that likely contributes to maintaining the contrast of synaptic weight between strengthened and weak synapses within an active ensemble.

1. Input-specificity of late phase plasticity: a fascinating long-term biochemical challenge Clinical case studies and animal lesion experiments have indicated the critical importance of the hippocampus in associative learning and formation of episodic memory [1]. During learning and memory, it has been suggested that the coordinated electrical activity of hippocampal neurons translates information about the external environment into internal neuronal representations [2]. A widely held hypothesis posits that plasticity at the synaptic level is a key feature that critically modulates such representations of the external environment within a circuit [3]. Thus, ever since long-term potentiation (LTP) [3–5] and long-term depression (LTD) [6–8] were discovered, one of the outstanding questions has been to pin down the cellular or the subcellular location of these plastic changes, and to understand how these events govern the formation of ‘engrams’ (or ensembles of active neurons contributing to the representation of a memory event) within various brain areas [9–11]. While engrams were originally thought to be formed at the cellular level, the discovery of the synaptic origin and the input-specificity of LTP and LTD induction called for a cell biological re-examination of the spatio-temporal dynamics of the initial plastic signal processing. How rapidly induced and sustained is the original plasticity signal? Is this localized to the plastic synapse or does the signal diffuse out? What then is the molecular substrate for the persistence of spine-level input-specific changes following plasticity? How does this relate to the original plasticity signal? What is the relationship between a cellular-level engram and synaptic plasticity?

& 2013 The Author(s) Published by the Royal Society. All rights reserved.


‘synaptic capture’

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Figure 1. A biochemical framework to account for a late phase of inputspecific plasticity that persists beyond the lifetime of a local synaptic input-correlated event (‘tagging’) and requires a cellwide mechanism such as nuclear transcription or new protein synthesis (formation of a ‘memory trace’). Sustainable synaptic tags are created following input-specific plasticity induction in a spine-restricted manner. While this tag is being maintained at the synapses, memory traces are further induced in parallel in the soma, via nuclear transcription and new protein synthesis. Before the lifetime of the tag ceases, the newly induced memory traces are ‘captured’ at or near the stimulated synapses of origin. Provided that there is a molecular signalling mechanism to reliably couple the ‘synapses-to-nucleus’ (many-to-one) pathway with the countergradiented ‘from nucleus-back-to-synapses’ (one-tomany) pathway, the longer protein localization lifetime of the ‘captured traces’ can outlast the relative transience of the synaptic tags. (Online version in colour.) largely elusive to date (figure 1 ‘synaptic capture’ question), although several candidate molecules have already been postulated as either a synaptic tag or a putative PRP [28]. Better understanding of these issues will certainly necessitate intensive investigation of the cell biological signalling crosstalk between many active synapses and the neuronal soma. Untangling such a long-distance, two-way communication route is of critical significance, as this may lie at the heart of the persistence of local synaptic changes following plasticity and during memory formation [25,26,29]. Additionally, however, we should keep in mind, and not underestimate, the formal (and non-mutually exclusive) possibility that a tiny amount of well-positioned molecular alterations in the plastic synapse may still strongly influence perpetuation of an ongoing local change in synaptic efficacy [30–32].

3. Addressing the ‘many-to-one’ question: defining a CaMKK–CaMKIV –CREB –SARE– Arc pathway critical for the late phaseplasticity and long-term memory signalling Over the past years, many groups have attempted to systematically investigate the molecular basis for the signalling from

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A large number of past works are in keeping with the idea that once synaptic plasticity is induced, the consolidation and the maintenance of such a new plasticity may involve additional molecular processes that necessitate active mRNA and new protein synthesis at the nucleus and the soma of the cell [9–13]. Indeed, plasticity-inducing synaptic activity was also shown to control the expression of many genes encoding synaptic proteins, ion channels, kinases or immediate early genes (IEGs) [3,13–15]. Some of these have been shown to be important for memory formation [16–18]. Behavioural experiments also suggest the critical role of activity-dependent transcription, new protein synthesis and further translational control in synaptic plasticity and memory [19–24]. Thus, it is likely that the proper regulation of the bidirectional signalling between the synapses and the nucleus is essential for the generation and persistence of memory. Are the changes induced by synaptic plasticity then somehow rendered persistent through a local, synapse-autonomous mechanism? Or alternatively, are robust and input-specific changes in synaptic efficacy accompanied by input-non-selective new transcription and new protein translation, which then together transform an otherwise transient plasticity into a long-lasting and stable one (figure 1, presence of a ‘many-toone’-type route between many plastic synapses and one neuronal soma responsible for triggering transcription)? How can a cellwide, synapse-unrestricted, mechanism, such as activitydependent gene expression or protein synthesis, possibly contribute to preserving input-specificity of the persistence of plastic changes (figure 1, presence of a ‘one-to-many’-type route to account for one soma-driven responses contributing to the input-specific maintenance of plasticity at many synapses)? A hypothesis called ‘synaptic tagging and capture’ has been proposed to provide a tangible framework to understand these ideas [25– 28], based on the intriguing observation that a strong plasticity event, through new gene expression and protein synthesis, could render persistent a temporally close weak plasticity event, which otherwise would have remained transient [25,28]. To account for this, it was speculated that a synaptic ‘tag’ which is long-lasting, but not permanent, is created at or near the synapses where synaptic plasticity is also induced. When a strong stimulus (which could be a plasticity-inducing stimulus on its own) is triggered within a limited time window of the original plasticity (such as within 60 min before or after the original plasticity stimulus), this triggers a strong transcriptional and translational response, which is sufficient to result in the subsequent delivery and targeting of new synthesized plasticity-related proteins (PRPs) from the soma towards the synapses where the original plasticity was induced. In this ‘synaptic tagging and capture’ hypothesis, the state of the synaptic tag, via a functional interaction (or ‘capture’) of the PRP, determines the ultimate persistence of the plastic changes [25–28]. However, the molecular basis for such a ‘synaptic tagging and capture’ hypothesis has remained

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2. Necessity for a crosstalk between synapses and the neuronal soma: a long-distance, two-way communication at the heart of the persistence of local synaptic changes following plasticity and during memory formation


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Figure 2. CREB is a unique transducer of long-term memory at the interface of ‘many-to-one’ and ‘one-to-many’ signalling. (a) CREB activation in the soma is rapidly triggered via a CaMKK – CaMKIV cascade, together with the local induction of input-specific synaptic plasticity. (b) An activity-dependent, combinatorial, CREB/MEF2/SRF-mediated transcription factor code triggers induction of a memory trace candidate protein Arc/Arg3.1 via the synaptic activity-responsive element (SARE) within a distal enhancer region of the Arc gene.

synapses to the nucleus that accompanies plastic changes at the synapses. Among many gene expression pathways present in neurons, the activation pathway of the transcription factor CREB is arguably one of the most studied activity-dependent synapses-to-nucleus signalling mechanisms [9,11–15,33–35]. Our earlier study thus uncovered an activity-dependent protein kinase cascade CaMKK–CaMKIV that critically controls the amplitude and time course of CREB phosphorylation downstream of synaptic activity (figure 2a) [36–38]. Consistently, a/d-CREB-null mice [33], CaMKIV-null mice [39] and knockout mice for either CaMKK-a [40,41] or CaMKK–b [42] all showed specific defects in long-term memory. Alternative routes of CREB activation include a cAMP–PKA pathway, and a Ras–MEK–Erk pathway [12,13,34], and the molecular dissection of these differential activation routes within the brain at the circuit level is still eagerly awaited. A large amount of effort has also been spent on identifying an exhaustive list of all the putative target genes for CREB

[43–45]. It remains to be clarified, however, how many of these will be critical for the late phase of long-term plasticity and long-term memory. One likely target molecule is brainderived neurotrophic factor (BDNF), a secreted peptide growth factor, and the role of CREB in activity-dependent stimulation of several alternative promoters for the gene encoding the neurotrophic factor BDNF has indeed been thoroughly investigated [46]. BDNF’s role in synaptic tagging and capture has also been shown [47–49]. Another possible candidate is the IEG Arc/Arg3.1 [50,51], a gene whose expression is widely used as a biological marker to map spatial representation of active neurons in fixed brain samples [52,53], and whose deletion has led to loss of long-term memory in mice [29]. By carefully examining the promoter and the distal regulatory elements critical for activity-dependent neuronal expression, we were indeed able to identify a CRE half-site that functioned as a genuine CREBregulated locus, within the synaptic activity-responsive element

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synaptic strength change

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synaptic activity


Despite the excitement about IEG mapping results which were consistent with the idea that Arc may be one of the memory trace proteins critical for memory formation, the molecular function of Arc has remained, however, enigmatic. Indeed, several studies showed that this putative memory trace-coding protein Arc, despite being strongly upregulated by synaptic activity that induced persistent forms of plasticity and learning [15,52,53], also critically contributed to weakening synapses by promoting AMPA receptor endocytosis during various forms of synaptic plasticity [18,57–59]. To address this incongruence, we directly imaged plasticityinduced Arc trafficking from the soma to the dendrites and back to the synapses [60]. Contrary to expectations that Arc may be recruited into the potentiated synapses through an orthodox synaptic tagging and capture mechanism, we instead found a preferred targeting of Arc to inactive synapses (figure 3). This unexpected result was mediated via Arc’s high affinity interaction with an inactive, CaM-unbound form of Ca2þ/ calmodulin-dependent protein kinase (CaMK)IIb [60]. Consistently, the degree of synaptic Arc accumulation was more sustained during a period of inactivity following strong induction, and in fact correlated with removal of surface GluA1 from individual synapses. A lack of CaMKIIb either in vitro or in vivo resulted in loss of Arc upregulation in the silenced synapses [60]. These findings provide compelling molecular evidence for an ‘inverse’ synaptic tagging mechanism that enables Arc to specifically target the unpotentiated synapses that contains more inactive CaMKIIb. Arc targeting to inactive synapses will promote the clearance of surface AMPA receptors at the inactive synapses, and thereby help maintain the contrast of synaptic weight between strengthened and weak synapses (figure 3) [60,61]. At the circuit and systems levels, this may subserve memory consolidation by preventing undesired synaptic enhancement at weak synapses, while sparing potentiated synapses. For inactive CaMKIIb to be able to fulfil the role of an inverse synaptic tag vis a` vis of induced Arc protein, any synaptic activity that is below the threshold of LTP induction should in principle do little to perturb CaMKII inactivity. Directly

4 synaptic tagging

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Figure 3. Synaptic tagging and inverse synaptic tagging: a putative two-bit tagging code for securing the persistence of an input-specific memory engram. Recent findings collectively suggest two modes of tagging synapses as a function of synaptic input during induction of LTP. The process of synaptic tagging involves modification of the spine context within which LTP has been induced (red tag: red, 1; green, 0 state). The capture of a memory trace (blue circle) to the vicinity of the tags, either by physical or functional interaction, will ensure that the strengthening of the LTP synapses will persist over time even after the lifetime of the tags has elapsed. In parallel to this, the process of inverse synaptic tagging involves an inverse tag (green tag: red, 0; green, 1 state) that will be present only in the nonpotentiated synapses, likely in the neighbourhood of LTP synapses, and which will capture/interact with a memory trace (yellow triangle). Compared with the basal state (no tags: red, 0; green, 0 state), the sustained lack of plasticity, hence the maintenance of an inverse tag, in the spines adjacent to the LTP synapses, will ensure that the weakened state (red, 0; green, 1 state) or the lack of potentiation will persist in those weak synapses through the action of an inverse tag-compliant memory trace (yellow triangle). Arc fulfils the role of a memory trace protein that interacts with CaM-unbound CaMKIIb acting as an inverse tag (green). Although more experiments are needed to test this, we hypothesize that red tags and green tags may transiently coexist in the same spines in an unstable and neutral state (both tags: red, 1; green, 1 state), when activated synapses slowly become inactive, or when inactive synapses become suddenly activated. The parallel onset of synaptic tagging and inverse synaptic tagging may thus provide a two-bit tagging code (red for tagging and green for inverse tagging) for securing the persistence of an input-specific memory engram, and facilitate the maintenance of a strong-to-weak contrast of synaptic weights within active neurons. addressing this question has become possible very recently, through novel techniques that enable direct measurement of enzymatic activities in situ. Using fluorescence resonance energy transfer (FRET) imaging and fluorescence lifetime microscopy measurements, direct measurements of the enzymatic activity of CaMKIIa with single spine resolution demonstrated [62,63] and confirmed some earlier suggestions [64] that the activation kinetics of CaMKIIa, a critical molecular switch involved in the induction of LTP [4,5,65,66], was very fast (within seconds) and input-specific (figure 4 top panels). Inconsistent with some predictions [30, see also 67], however, the deactivation of CaMKIIa after cessation of LTP induction was also fast, within a minute (figure 4) [62,63]. The same conditions of stimuli that triggered sustained morphological plasticity in a high-frequency- and input-dependent manner also triggered activation of CaMKIIa, but the former far outlasted the latter [63]. Thus, CaMKIIa genuinely functioned as a synaptic sensor for high-frequency input (figure 4 top panels), and was an enzyme that decodes both input frequency and numbers [63], but its activity was short-lived and did not appear to encode the plasticity induction per se. As an

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4. Synaptic tagging and inverse synaptic tagging: a putative two-bit tagging code for securing the persistence of an input-specific memory engram?

two co-existing tagging mechanisms activated inactive synapse synapse (1 0) (0 1)


(SARE), a distal enhancer region located at about 7-kb upstream of the Arc’s transcription start site [54,55]. Strikingly, the SARE of the Arc gene consisted of a unique cluster of binding sites for CREB, MEF2 and SRF/TCF, each of which cooperatively contributed to converting synaptic inputs into a transcriptional output (figure 2b). Multiplexing SARE and fusing this to the minimal promoter of the Arc gene has enabled us to create a synthetic promoter, which we named enhanced SARE (E-SARE). This artificial promoter was about 30 times more potent than the c-fos promoter and is expected to serve as a useful means to map and record from activity-regulated neurons and circuits in various areas of the brain in vivo [56]. Future studies will reveal whether neurons in which synaptic activity-induced CREB activation and Arc expression are enhanced truly represent part of a functional ensemble of active neurons within a memory circuit, as suggested by the IEG mapping analyses [52,53].


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Figure 4. Dual FRET-based direct measurements of CaMKIIa and calcineurin at synapses following plasticity-inducing stimuli (modified with permission from [63]). Demonstration of input-specific, single spine-restricted, transient activation of CaMKIIa and calcineurin following plasticity-inducing stimuli using dual FRET with optical manipulation (dFOMA) imaging techniques. Top panels: CaMKIIa activity (calculated as normalized FRET ratio of the RS-K2a probe) recorded following 5 Hz (left) or 20 Hz stimuli (right); bottom panels, calcineurin activity (calculated as normalized FRET ratio of the RY-CaN probe) recorded following 5 Hz (left) or 20 Hz MNI-glutamate uncaging (GU) stimuli (right). Utmost right graphs show amplitude comparisons between 5 and 20 Hz stimuli.

independent control for an alternative synaptic Ca2þ effector, calcineurin was shown to be activated at a much lower frequency and input numbers than CaMKIIa (figure 4 lower panels) [63]. While direct measurements of CaMKIIb are eagerly awaited as a next step, this recent evidence lends support to the idea that CaMKII activation may indeed gate the role of Arc in inverse synaptic tagging. A role for CaMKII has also been suggested in the original synaptic tagging [27,28]. Evidently, much work lies ahead to definitively establish the mechanisms and physiological significance of synaptic tagging [68] and inverse synaptic tagging [60]. Perhaps, simultaneous onset of both tagging mechanisms, in conjunction with the induction of LTP per se, may permit synapses to gain the ability to use a robust, two-bit tagging code for securing the persistence of an input-specific memory

engram (figure 3). Further investigation on both synaptic tagging and inverse synaptic tagging will undoubtedly shed more light on the fundamental role of new gene expression and of the guided targeting of new protein products to synapses as a molecular basis for memory allocation within an activated neuronal network [69]. Acknowledgements. We are grateful to Stuart Sharry for critical comments. We apologize to the many authors whom we could not cite due to space limitations. Funding statement. This work was supported in part by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Japan Society for Promotion of Science (M.N., H.O. and H.B.), awards from the Takeda Foundation (H.B.) and the Tokyo Society of Medical Sciences (H.F. and H.O.), a SICPMe JST-CONACyT collaborative grant (H.O. and H.B.) and a CREST investigatorship (H.B.).

References 1.

2.

Morris RG. 2006 Elements of a neurobiological theory of hippocampal function: the role of synaptic plasticity, synaptic tagging and schemas. Eur. J. Neurosci. 23, 2829 –2846. (doi:10.1111/j. 1460-9568.2006.04888.x) Abbott A. 2013 Neuroscience: solving the brain. Nature 499, 272 –274. (doi:10.1038/499272a)

3.

4.

Bliss TV, Collingridge GL. 1993 A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31 –39. (doi:10.1038/ 361031a0) Malenka RC, Nicoll RA. 1999 Long-term potentiation: a decade of progress? Science. 285, 1870 –1874. (doi:10.1126/science.285.5435.1870)

5.

6.

Bliss TV, Collingridge GL. 2013 Expression of NMDA receptor-dependent LTP in the hippocampus: bridging the divide. Mol. Brain 6, 5. (doi:10.1186/ 1756-6606-6-5) Bear MF, Abraham WC. 1996 Long-term depression in hippocampus. Annu. Rev. Neurosci. 19, 437 –462. (doi:10.1146/annurev.ne.19.030196.002253)

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normalized ratio

1.20

0.95 –0.5

RY-CaN (calcineurin)

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1.20 normalized ratio

RS-K2a (CaMKIIa)

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–0.15 2 mm


+0.15

+0.15


7.

9.

10.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

16, 89 – 101. (doi:10.1016/S0896-6273(00) 80026-4) Mermelstein PG, Bito H, Deisseroth K, Tsien RW. 2000 Critical dependence of cAMP response element-binding protein phosphorylation on L-type calcium channels supports a selective response to EPSPs in preference to action potentials. J. Neurosci. 20, 266 –273. Wei F, Qiu CS, Liauw J, Robinson DA, Ho N, Chatila T, Zhuo M. 2002 Calcium calmodulin-dependent protein kinase IV is required for fear memory. Nat. Neurosci. 5, 573–579. (doi:10.1038/nn0602-855) Mizuno K, Ris L, Sa´nchez-Capelo A, Godaux E, Giese KP. 2006 Ca2þ/calmodulin kinase kinase alpha is dispensable for brain development but is required for distinct memories in male, though not in female, mice. Mol. Cell. Biol. 26, 9094–9104. (doi:10.1128/MCB.01221-06) Blaeser F, Sanders MJ, Truong N, Ko S, Wu LJ, Wozniak DF, Fanselow MS, Zhuo M, Chatila TA. 2006 Long-term memory deficits in Pavlovian fear conditioning in Ca2þ/calmodulin kinase kinase alpha-deficient mice. Mol. Cell. Biol. 26, 9105– 9115. (doi:10.1128/MCB.01452-06) Peters M, Mizuno K, Ris L, Angelo M, Godaux E, Giese KP. 2003 Loss of Ca2þ/calmodulin kinase kinase beta affects the formation of some, but not all, types of hippocampus-dependent long-term memory. J. Neurosci. 23, 9752–9760. Impey S et al. 2004 Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions. Cell 119, 1041–1054. Zhang X et al. 2005 Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues. Proc. Natl Acad. Sci. USA 102, 4459– 4464. (doi:10.1073/pnas.0501076102) Benito E, Valor LM, Jimenez-Minchan M, Huber W, Barco A. 2011 cAMP response element-binding protein is a primary hub of activity-driven neuronal gene expression. J. Neurosci. 31, 18 237– 18 250. (doi:10.1523/jneurosci.4554-11.2011) Greenberg ME. 2006–2007 Signaling networks that control synapse development and cognitive function. Harvey Lect. 102, 73– 102. Barco A, Patterson SL, Alarcon JM, Gromova P, Mata-Roig M, Morozov A, Kandel ER. 2005 Gene expression profiling of facilitated L-LTP in VP16CREB mice reveals that BDNF is critical for the maintenance of LTP and its synaptic capture. Neuron 48, 123 –137. (doi:10.1016/j.neuron.2005.09.005) Lu Y, Ji Y, Ganesan S, Schloesser R, Martinowich K, Sun M, Mei F, Chao MV, Lu B. 2011 TrkB as a potential synaptic and behavioral tag. J. Neurosci. 31, 11762– 11771. (doi:10.1523/JNEUROSCI.2707-11.2011) Panja D, Bramham CR. In press. BDNF mechanisms in late LTP formation: a synthesis and breakdown. Neuropharmacology. (doi:10.1016/j.neuropharm. 2013.06.024) Lyford GL et al. 1995 Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched

6

Phil. Trans. R. Soc. B 369: 20130150

11.

24.

plasticity and memory. Neuron 61, 10 –26. (doi:10. 1016/j.neuron.2008.10.055) Gal-Ben-Ari S et al. 2012 Consolidation and translation regulation. Learn. Mem. 19, 410 –422. (doi:10.1101/lm.026849.112) Frey U, Morris RG. 1997 Synaptic tagging and long-term potentiation. Nature 385, 533–536. (doi:10.1038/385533a0) Martin KC, Kosik KS. 2002 Synaptic tagging: who’s it? Nat. Rev. Neurosci. 3, 813–820. (doi:10.1038/ nrn942) Redondo RL, Okuno H, Spooner PA, Frenguelli BG, Bito H, Morris RG. 2010 Synaptic tagging and capture: differential role of distinct calcium/ calmodulin kinases in protein synthesis-dependent long-term potentiation. J. Neurosci. 30, 4981– 4989. (doi:10.1523/JNEUROSCI.3140-09.2010) Redondo RL, Morris RG. 2011 Making memories last: the synaptic tagging and capture hypothesis. Nat. Rev. Neurosci. 12, 17 –30. (doi:10.1038/ nrn2963) Bito H. 1998 The role of calcium in activitydependent neuronal gene regulation. Cell Calcium 23, 143– 150. (doi:10.1016/S01434160(98)90113-0) Lisman J, Yasuda R, Raghavachari S. 2012 Mechanisms of CaMKII action in long-term potentiation. Nat. Rev. Neurosci. 13, 169 –182. Sacktor TC. 2012 Memory maintenance by PKMz: an evolutionary perspective. Mol. Brain 5, 31. (doi:10.1186/1756-6606-5-31) Bailey CH, Kandel ER, Si K. 2004 The persistence of long-term memory: a molecular approach to selfsustaining changes in learning-induced synaptic growth. Neuron 44, 49 –57. (doi:10.1016/j.neuron. 2004.09.017) Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G, Silva AJ. 1994 Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 79, 59 –68. (doi:10.1016/0092-8674(94)90400-6) Flavell SW, Greenberg ME. 2008 Signaling mechanisms linking neuronal activity to gene expression and plasticity of the nervous system. Annu. Rev. Neurosci. 31, 563 –590. (doi:10.1146/ annurev.neuro.31.060407.125631) Nonaka M. 2009 A Janus-like role of CREB protein: enhancement of synaptic property in mature neurons and suppression of synaptogenesis and reduced network synchrony in early development. J. Neurosci. 29, 6389– 6391. (doi:10.1523/ JNEUROSCI.1309-09.2009) Bito H, Deisseroth K, Tsien RW. 1996 CREB phosphorylation and dephosphorylation: a Ca2þ- and stimulus duration-dependent switch for hippocampal gene expression. Cell 87, 1203–1214. (doi:10.1016/S0092-8674 (00)81816-4) Deisseroth K, Bito H, Tsien RW. 1996 Signaling from synapse to nucleus: postsynaptic CREB phosphorylation during multiple forms of hippocampal synaptic plasticity. Neuron


8.

Malenka RC, Bear MF. 2004 LTP and LTD: an embarrassment of riches. Neuron 44, 5 –21. (doi:10.1016/j.neuron.2004.09.012) Collingridge GL, Peineau S, Howland JG, Wang YT. 2010 Long-term depression in the CNS. Nat. Rev. Neurosci. 11, 459– 473. (doi:10.1038/nrn2867) Kandel ER. 2001 The molecular biology of memory storage: a dialogue between genes and synapses. Science 294, 1030 –1038. (doi:10.1126/science. 1067020) Klann E, Sweatt JD. 2008 Altered protein synthesis is a trigger for long-term memory formation. Neurobiol. Learn. Mem. 89, 247–259. (doi:10.1016/ j.nlm.2007.08.009) Josselyn SA. 2010 Continuing the search for the engram: examining the mechanism of fear memories. J. Psychiatry Neurosci. 35, 221 –228. (doi:10.1503/jpn.100015) Silva AJ, Kogan JH, Frankland PW, Kida S. 1998 CREB and memory. Annu. Rev. Neurosci. 21, 127–148. (doi:10.1146/annurev.neuro.21.1.127) Bito H, Deisseroth K, Tsien RW. 1997 Ca2þ-dependent regulation in neuronal gene expression. Curr. Opin. Neurobiol. 7, 419–429. (doi:10.1016/S0959-4388 (97)80072-4) Morgan JI, Curran T. 1989 Stimulus-transcription coupling in neurons: role of cellular immediateearly genes. Trends Neurosci. 12, 459–462. (doi:10.1016/0166-2236(89)90096-9) Okuno H. 2011 Regulation and function of immediate-early genes in the brain: beyond neuronal activity markers. Neurosci. Res. 69, 175–186. (doi:10.1016/j.neures.2010.12.007) Silva AJ, Paylor R, Wehner JM, Tonegawa S. 1992 Impaired spatial learning in alpha-calciumcalmodulin kinase II mutant mice. Science 257, 206–211. (doi:10.1126/science.1321493) Paylor R, Johnson RS, Papaioannou V, Spiegelman BM, Wehner JM. 1994 Behavioral assessment of c-fos mutant mice. Brain Res. 651, 275 –282. (doi:10.1016/0006-8993(94)90707-2) Plath N et al. 2006 Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories. Neuron 52, 437– 444. (doi:10.1016/j.neuron.2006. 08.024) Davis HP, Squire LR. 1984 Protein synthesis and memory: a review. Psychol. Bull. 96, 518–559. (doi:10.1037/0033-2909.96.3.518) DeZazzo J, Tully T. 1995 Dissection of memory formation: from behavioral pharmacology to molecular genetics. Trends Neurosci. 18, 212–218. (doi:10.1016/0166-2236(95)93905-D) Mayford M, Abel T, Kandel ER. 1995 Transgenic approaches to cognition. Curr. Opin. Neurobiol. 5, 141–148. (doi:10.1016/0959-4388(95)80019-0) Wang SH, Redondo RL, Morris RG. 2010 Relevance of synaptic tagging and capture to the persistence of long-term potentiation and everyday spatial memory. Proc. Natl Acad. Sci. USA 107, 19 537– 19 542. (doi:10.1073/pnas.1008638107) Costa-Mattioli M, Sossin WS, Klann E, Sonenberg N. 2009 Translational control of long-lasting synaptic


52.

54.

55.

63. Fujii H, Inoue M, Okuno H, Sano Y, TakemotoKimura S, Kitamura K, Kano M, Bito H. 2013 Nonlinear decoding and asymmetric representation of neuronal input information by CaMKIIa and calcineurin. Cell Rep. 3, 978 –987. (doi:10.1016/j. celrep.2013.03.033) 64. Lengyel I, Voss K, Cammarota M, Bradshaw K, Brent V, Murphy KP, Giese KP, Rostas JA, Bliss TV. 2004 Autonomous activity of CaMKII is only transiently increased following the induction of long-term potentiation in the rat hippocampus. Eur. J. Neurosci. 20, 3063 –3072. (doi:10.1111/ j.1460-9568.2004.03748.x) 65. Malinow R. 2003 AMPA receptor trafficking and long-term potentiation. Phil. Trans. R. Soc. Lond. B 358, 707–714. (doi:10.1098/rstb.2002.1233) 66. Deisseroth K, Bito H, Schulman H, Tsien RW. 1995 Synaptic plasticity: a molecular mechanism for metaplasticity. Curr. Biol. 5, 1334–1338. (doi:10.1016/S0960-9822(95)00262-4) 67. Coultrap SJ, Bayer KU. 2012 CaMKII regulation in information processing and storage. Trends Neurosci. 35, 607 –618. (doi:10.1016/j.tins.2012.05.003) 68. Okada D, Ozawa F, Inokuchi K. 2009 Input-specific spine entry of soma-derived Vesl-1S protein conforms to synaptic tagging. Science 324, 904–909. (doi:10.1126/science.1171498) 69. Silva AJ, Zhou Y, Rogerson T, Shobe J, Balaji J. 2009 Molecular and cellular approaches to memory allocation in neural circuits. Science 326, 391 –395. (doi:10.1126/science.1174519)

7

Phil. Trans. R. Soc. B 369: 20130150

53.

56. Kawashima T et al. 2013 Functional labeling of neurons and their projections using the synthetic activity-dependent promoter E-SARE. Nat. Methods 10, 889– 895. (doi:10.1038/nmeth.2559) 57. Chowdhury S, Shepherd JD, Okuno H, Lyford G, Petralia RS, Plath N, Kuhl D, Huganir RL, Worley PF. 2006 Arc/ Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking. Neuron 52, 445–459. (doi:10.1016/j.neuron.2006.08.033) 58. Shepherd JD, Rumbaugh G, Wu J, Chowdhury S, Plath N, Kuhl D, Huganir RL, Worley PF. 2006 Arc/Arg3.1 mediates homeostatic synaptic scaling of AMPA receptors. Neuron 52, 475– 484. (doi:10.1016/j.neuron.2006.08.034) 59. Rial Verde EM, Lee-Osbourne J, Worley PF, Malinow R, Cline HT. 2006 Increased expression of the immediate-early gene arc/arg3.1 reduces AMPA receptor-mediated synaptic transmission. Neuron 52, 461– 474. (doi:10.1016/j.neuron.2006.09.031) 60. Okuno H et al. 2012 An inverse synaptic tagging of inactive synapses via dynamic interaction of Arc/Arg3.1 with CaMKIIb. Cell 149, 886 –898. (doi:10.1016/j.cell.2012.02.062) 61. Kim R, Okuno H, Bito H. 2012 Deciphering the molecular rules governing synaptic targeting of the memory-related protein Arc. Commun. Integr. Biol. 5, 496– 498. (doi:10.4161/cib.20853) 62. Lee SJ, Escobedo-Lozoya Y, Szatmari EM, Yasuda R. 2009 Activation of CaMKII in single dendritic spines during long-term potentiation. Nature 458, 299 –304. (doi:10.1038/nature07842)


51.

in neuronal dendrites. Neuron 14, 433– 445. (doi:10.1016/0896-6273(95)90299-6) Link W, Konietzko U, Kauselmann G, Krug M, Schwanke B, Frey U, Kuhl D. 1995 Somatodendritic expression of an immediate early gene is regulated by synaptic activity. Proc. Natl Acad. Sci. USA 92, 5734–5738. (doi:10.1073/pnas.92.12.5734) Guzowski JF, McNaughton BL, Barnes CA, Worley PF. 1999 Environment-specific expression of the immediate-early gene Arc in hippocampal neuronal ensembles. Nat. Neurosci. 2, 1120 –1124. (doi:10.1038/16046) Ramirez-Amaya V, Vazdarjanova A, Mikhael D, Rosi S, Worley PF, Barnes CA. 2005 Spatial exploration-induced Arc mRNA and protein expression: evidence for selective, network-specific reactivation. J. Neurosci. 25, 1761–1768. (doi:10. 1523/jneurosci.4342-04.2005) Kawashima T, Okuno H, Nonaka M, Adachi-Morishima A, Kyo N, Okamura M, Takemoto-Kimura S, Worley PF, Bito H. 2009 Synaptic activity-responsive element in the Arc/Arg3.1 promoter essential for synapse-tonucleus signaling in activated neurons. Proc. Natl Acad. Sci. USA 106, 316–321. (doi:10.1073/pnas. 0806518106) Inoue M, Yagishita-Kyo N, Nonaka M, Kawashima T, Okuno H, Bito H. 2010 Synaptic activity responsive element (SARE): a unique genomic structure with an unusual sensitivity to neuronal activity. Commun. Integr. Biol. 3, 443–446. (doi:10.4161/ cib.3.5.12287)

Postnatal development of the hypothalamic ventromedial nucleus: neurons and synapses.

Synapses between interneurons in the lateral geniculate nucleus of monkeys.

Associative Learning Drives the Formation of Silent Synapses in Neuronal Ensembles of the Nucleus Accumbens.

Characterization of synapses in the rat subnucleus centralis of the nucleus tractus solitarius.

Projections from the central amygdaloid nucleus to the precuneiform nucleus in the mouse.

Synaptic consolidation: from synapses to behavioral modeling.

Synapses in the interpeduncular nucleus: electron microscopy of normal and habenula lesioned rats.

Physiological evidence of formation of new synapses from cerebrum in the red nucleus neurons following cross-union of forelimb nerves.

A projection from the parabigeminal nucleus to the pulvinar nucleus in Galago.

Vestibular nucleus neurons relaying excitation from the anterior canal to the oculomotor nucleus.

Plexin-B1 signalling promotes androgen receptor translocation to the nucleus.

Dendritic geometry shapes neuronal cAMP signalling to the nucleus.

Remodeling of glial coverage of glutamatergic synapses in the rat nucleus tractus solitarii after ozone inhalation.

Neurochemical properties of the synapses between the parabrachial nucleus-derived CGRP-positive axonal terminals and the GABAergic neurons in the lateral capsular division of central nucleus of amygdala.

Synapses formed by olivocochlear axon branches in the mouse cochlear nucleus.

Investigations on day-night differences of vesicle densities in synapses of the rat suprachiasmatic nucleus.

Physiological properties of the newly formed cortico-rubral synapses of red nucleus neurons due to collateral sprouting.

Projections from the lateral nucleus of the trapezoid body to the medial superior olivary nucleus in the gerbil.

Topographical projections from the thalamus, subthalamic nucleus and pedunculopontine tegmental nucleus to the striatum in the Japanese monkey, Macaca fuscata.

Serotonergic projections from the midbrain periaqueductal gray and nucleus raphe dorsalis to the nucleus parafascicularis of the thalamus.

The organization of plasticity in the cerebellar cortex: from synapses to control.

Autoradiographic evidence for a discontinuous projection to the caudate nucleus from the centromedian nucleus in the cat.

Met-enkephalin-Arg6-Gly7-Leu8- and substance P-containing projections from the nucleus preopticus medianus to the paraventricular hypothalamic nucleus.

An electron microscope study of the red nucleus in the cat, with special reference to the quantitative analysis of the axosomatic synapses.