BNS Literature Review Metaplasticity: A new frontier in the neural representation of Dano Morrison1 1Department of Psychology, University of British Columbia

Edited by: Jenn Ferris, Department of Psychology, University of British Columbia. Received for review January 10, 2012, and accepted March 2, 2012. Copyright: © 2012 Morrison. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivates License, which permits anyone to download and share the article, provided the original author(s) are cited and the works are not used for commercial purposes or altered in any way.

Abstract , the modification of the strength of connections between , is widely accepted to be essential for information storage in the and is thought to form the basis of and memory. However, in order for the richness of learning and memory to emerge from the long-term potentiation and depression of , regulatory mechanisms must exist. Metaplasticity, the phenomenon of previous synaptic activity modulating the future synaptic plasticity of a , might answer questions about how synaptic plasticity is regulated in order to create meaningful, coordinated changes in neural activity. There are many different proposed contributors to metaplasticity, including the NMDA and AMPA receptors, epigenetics, and neurotrophins. Although the way in which all these factors interact remains enigmatic, metaplasticity appears to play a role in learning, possibly by serving to control neuronal 'learning modes.'

Keywords: metaplasticity, plasticity, memory, learning, long-term potentiation

The seemingly simple question, “how is ability of neural connections to change by information stored in the nervous system?” strengthening or weakening, is revolutionary has proven difficult to answer in the nearly in its potential to provide a physiological five decades in which the biological basis of explanation for learning, but its mechanisms memory has been studied. Behavioural have yet to be fully understood. How the observation of learning and memory has complexity of learning and memory can arise been successful in characterizing many of from such simple changes is one the most the functional aspects of memory; short- fascinating questions in neuroscience. term memory, long-term memory, and For the purposes of this review, conditioning have all been well studied. synaptic plasticity is defined as long-term However, due to technological constraints potentiation (LTP) and the complementary and the complexity of neural systems, process of long-term depression (LTD) of knowledge of the neurobiological connections between neurons. First underpinnings behind learning and memory discovered in rat hippocampal experiments is severely lacking. Synaptic plasticity, the in 1964, LTP is the process by which high

Corresponding Author: Dano Morrison E-mail: [email protected]

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frequency electrical stimulus delivered to a which high or low frequency stimulation bundle of axons results in increased affects the extent with which a neuron will sensitivity or 'potentiation' of those neurons undergo LTP or LTD in the future. Between to stimulation. Between two synapsed cells, two synapsed neurons, this could manifest this means that if one neuron repeatedly as a greater frequency of stimulation stimulates another, the first neuron can required to induce LTP in a neuron that has more easily excite the second neuron. This already been potentiated. The specific results in the strengthening of synaptic mechanisms and functions of metaplasticity transmission between these two remain unclear, but it appears to be critical communicating neurons. Because this in maintaining synaptic memory traces and potentiation was observed to last for days keeping synaptic plasticity occurring within a (up to an entire year in one study), it was tight, dynamic range. If synaptic plasticity is believed to be the primary process through the neural representation of firing history, which memory traces were encoded in then metaplasticity is the neural history of neural structures (Abraham, 2002). This that plasticity. effect, which was first discovered by Bliss and Lomo in 1964, caused great excitement Synaptic Plasticity: Potentiation and because it supported an important idea that Depression had been circulating—that persistent Neurons can form thousands of connections changes in the strength of connections with neighbouring cells between specialized between neurons form the basis of learning cell junctions called synapses. Neurons and memory. transmit information through action- LTD is the reverse of LTP; wherein potentials (APs), large waves of electrical synapses are depressed and exhibit reduced activity that travel down the neuron's axon sensitivity following long-term, low- and stimulate the awaiting dendrites of that frequency stimulation. Less extensively neuron's synaptic partners. Importantly, studied, LTD is believed to be critical in the action potentials are all-or-none responses; ability of neural systems to refine their once the threshold level of stimulation of circuits for efficiency. the neuron is reached, the action potential Although the brain's ability to learn, will fire with the exact same intensity, remember, and adapt to stimuli cannot be regardless of the magnification of the explained entirely in terms of synaptic triggering stimuli. This means that the plasticity, most memory research today is frequency, not the intensity, of action based on the assumption that plasticity is potential firing becomes the primary way the foundation from which all these abilities through which out-going signal strength is arise. For a comprehensive review on the encoded in neural systems. role of LTP and LTD in learning and memory The is the primary junction of see Lynch (2004). information transfer. When an AP reaches This review will address the basic the synapse of the transmitting or mechanisms of synaptic plasticity and presynaptic neuron, neurotransmitters are describe metaplasticity, a recently released which stimulate much smaller discovered and exciting phenomenon which electrical signals of variable strength in the regulates and integrates synaptic plasticity receiving, or postsynaptic, neuron. Unlike over time. Metaplasticity is the process in APs, these postsynaptic potentials (PSPs) can

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BNS METAPLASTICITY Literature Review vary in strength depending on a number of primarily occurs through the rapid flow of factors, such as the number and sensitivity ions through ion-permeable, ionotropic of postsynaptic neurotransmitter receptors. receptors. At glutamine-based synapses in These PSPs then travel to the cell body and, the , which are known to be much like how smaller waves in the ocean critical in learning and memory, there are combine to form larger waves, summate two important types of ionotropic receptors: into large membrane potentials which push NMDA (N-methyl-D-aspartate) and AMPA the total membrane depolarization towards (α-amino-3-hydroxy-5-methyl-4- or away from the threshold at which an AP is isoxazolepropionic acid). These receptors, created (Pinel, 2007). With hundreds of though both responsive to glutamine, have these incoming signals converging with several important functional differences. different strengths and frequencies, there AMPA receptors (AMPARs), will always allow exists a staggering amount of computational ion flow and cause local PSPS when power within each neuron. glutamate binds to them, while NMDA Synaptic plasticity is simply the process receptors (NMDARs) possess a voltage- by which the sensitivity of these synaptic dependent magnesium gate and will only connections alters according to their level of open when binding is coupled with a activity. “Those that fire together, wire significant amount of postsynaptic together” is a common expression depolarization (Pinel, 2007). The interplay of describing this process in which the synapses these two of receptors is crucial for many between neurons that often fire together neuronal functions, including synaptic are strengthened, such that it becomes plasticity easier for the presynaptic neuron to activate During high-frequency stimulation, the postsynaptic neuron. This is glutamate binding to AMPA receptors causes accomplished by a change in synaptic a large number of ions to enter the efficacy, defined as the amplitude of the PSP postsynaptic neuron, which initiates PSPs generated upon activation by presynaptic and opens NMDAR channels by depolarizing firing. LTP strengthens PSPs and LTD the postsynaptic environment. With their weakens them. In this way, the brain is able channels open, NMDARs are free to allow to adapt to organize its firing and adapt to the influx of calcium ions into the synapse. new patterns of stimulation. Calcium (Ca2+) influx leads to the How does LTP occur? When researchers phosphorylation of regulatory protein first set out the answer this question, they kinases, initiating both an early and a late- hoped to pinpoint either presynaptic or phase of LTP. First, in early-phase LTP, these postsynaptic changes as leading to changes protein kinases (e.g calcium-dependent in synaptic efficacy; however, it appears that protein kinase II (CaMKII)), increase the both presynaptic and postsynaptic changes sensitivity of existing AMPARs and recruit are involved. Because primarily postsynaptic new receptors to the synapse (Malenka & changes appear to be involved in Bear, 2004). This almost immediate increase metaplasticity, only postsynaptic LTP in both AMPAR density and sensitivity leads mechanisms will be discussed here and to a stronger postsynaptic response to the readers interested in presynaptic same presynaptic stimulus, effectively mechanisms should consult Castillo (2012). creating a memory trace within the neuron. In the synapse, the generation of PSPs In what is known as late-phase LTP, a

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cascade of secondary messengers travel to desensitization and removal (Malenka & the cell nucleus, initiating gene expression Bear, 2004). The selective weakening of and protein synthesis, facilitating increased synapses through LTD is believed to be production of AMPAR proteins and other important for the constructive use of LTP. synaptic proteins (Lynch, 2004). Late-phase Indeed, if synapses continued to increase in LTP often results in an increased strength, they would ultimately reach a postsynaptic surface area and a greater ceiling level of synaptic efficacy which would number of synaptic vesicles, which further prevent the encoding of new information It amplifies the ability of the presynaptic is important to note that the complete neuron to excite the postsynaptic neuron picture of these mechanisms, including the (Desmond & Levy, 1988). Both early- and involvement of other supplementary late-phase LTP are implicated in learning and mechanisms, is much more complex than memory by enhancing retention of a task for described here and despite being an area of the first few minutes after it is learned while active research, is beyond the scope of this also making arrangements for the persistent article. For further detail on LTD retention of that learning. mechanisms, readers should consult Long-term depression, the weakening Collingridge (2010). of synaptic efficacy following prolonged low- frequency stimulation, has not been studied The BCM Theory: Thresholds of as extensively as LTP, but its basic mechanics Plasticity appear similar. During low-frequency In order to describe how metaplasticity stimulation, there is a relatively low degree affects the induction of synaptic plasticity, it of postsynaptic depolarization and thus a is appropriate to first address the BCM much smaller amount of NMDAR activation theory of plasticity thresholds. During and Ca2+ influx. Interestingly, rather than synaptic firing, increases in postsynaptic Ca2+ simply leading to a reduced degree of LTP, cause changes in synaptic efficacy: but if Ca2+ low levels of Ca2+ appear to have the is the stimulus for both LTP and LTD, then opposite effect entirely. While high levels of what determines whether LTP or LTD will be Ca2+ phosphorylate regulatory kinases, low induced? Because the effect of Ca2+ is Ca2+ levels promote their concentration-dependent, there seems to be dephosphorylation. This leads to a decrease a threshold concentration that determines in synaptic efficacy via AMPAR whether potentiation, depression, or no change in synaptic efficacy will occur. The Bienenstock-Cooper-Munro (BCM) model best characterizes this threshold. The BCM model (see figure 1) describes a relationship between postsynaptic response (x-axis on figure) and change in postsynaptic strength (Φ) with two key features. First, a threshold exists (θM) above which the synapse will be strengthened (LTP), and below which it will be weakened Figure 1. The BCM model function depicting postsynaptic activity (X), change in postsynaptic (LTD). Second, this threshold is not static, efficacy (Φ), and plasticity threshold (θM). but shifts in response to the average

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BNS METAPLASTICITY Literature Review frequency of presynaptic stimulation the same pathway (Huang, Colino, Selig, & (Bienenstock, Cooper, & Munro, 1982). In Malenka, 1992). This effect lasted for this way, an increase in sensitivity following upwards of thirty minutes, was dependent LTP induction will not cause even more LTP on NMDAR activation, and seemed to in a cycle of positive feedback and lead to represent a shift in the BCM plasticity excitotoxicity (cellular toxicity involving threshold since the inhibition could be overactivation of glutamate receptors), and overcome eventually by increasing the a loss of meaningful input from the synapse. intensity of stimulation. These experiments A sliding threshold allows synaptic plasticity were the first to demonstrate that 'priming' to function as a synaptic 'novelty detector', stimuli, whether it induces LTP or not, can with the threshold being equal to the cause covert changes in the synapse which average level of activity so that LTP and LTD will affect subsequent plasticity responses. are only induced during significant bursts of This effect was dubbed “metaplasticity” in stimulation frequency. because of its higher-order nature and was The BCM model was constructed based met with much excitement because of its on observation and mathematical analysis of implications for a mechanism of synaptic synaptic plasticity with little explanation for plasticity control similar to what had been physical mechanisms. However, following proposed by the BCM theory. the discovery of metaplasticity, it has Metaplasticity is often defined as “the become clear that synaptic plasticity plasticity of synaptic plasticity.” In other regulation is not as simple as the BCM model words, synaptic plasticity itself is plastic proposes. (capable of change), and metaplasticity is its modulation by a cell's prior history of Metaplasticity: Making Plasticity Make activity. Metaplastic changes are subtle yet Sense enduring, and allow synaptic events at a In an early experiment on LTP, researchers single point in time to regulate synaptic were surprised to find that increasing the processing minutes, hours, or even days permeability of NMDARs to Ca2+ later. For example, if a synapse has just paradoxically seemed to prevent LTP undergone LTP, the same stimulus delivered induction (Coan, Irving, & Collingridge, only minutes later will fail to elicit the same 1989). This conflicted with what was known degree of potentiation, and may even cause about LTP at the time; NMDAR activation depression. Importantly, metaplasticity can leads to LTP so it was expected that greater be monosynaptic, effective at one synapse NMDAR permeability, and thus greater Ca2+ only, or heterosynaptic, effecting influx, would strengthen LTP. These neighbouring synapses as well (Abraham, researchers correctly concluded that 2008). NMDAR activation could somehow have an Functionally, metaplasticity allows inhibitory effect on LTP despite its central neurons to integrate plasticity-relevant role in LTP induction, but were unable to signals over time, encouraging gradual and specify how. Research by Huang et al. in meaningful neural change. Furthermore, 1992 clarified this effect when they metaplasticity maintains plasticity within a demonstrated that induction of LTP by a dynamic range and prevents destructive strong stimulus could be inhibited if a weak feedback cycles that may lead to either stimulus had been previously delivered to excessive or insufficient activation. The

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higher-order, 'meta', nature of this effect is (Zhang et al., 2005). This is plausible since exciting not only because of its importance CaMKII is crucial in both early- and late- to organized functioning of plasticity, but phase LTP; however, it is unclear whether also because it suggests that neurons retain the activation of CaMKII during a trace of their own activity. metaplasticity is involved or conflicts with its transient phosphorylation during LTP Mechanisms of Metaplasticity induction. Recent electrostatic imaging studies have revealed that CaMKII is an NMDAR: LTP Inhibition. Much like synaptic impressively complex enzyme possessing plasticity itself, metaplasticity can either two sets of six binding domains, so it is quite have potentiating or depressing effects. As possible that it may be activated at multiple described by the BCM model, a decrease in sites independently (Craddock, Tuszynski, & successive LTP (a shift of the threshold θM to Hameroff, 2012). This is a fascinating area the right, Figure 1) appears to be based on for further research, not only to clarify NMDA activity, and lasts from 30-90 minutes CaMKII's involvement in metaplasticity, but (Huang et al., 1992). There have been two also because these multiple binding domains proposed mechanisms for how NMDAR may be another site of information storage activation may lead to an increase in the in the nervous system. plasticity threshold. One theory was based on the observation that NMDARs themselves mGluR: LTP Facilitation. The idea that will occasionally become desensitized after metaplasticity facilitates LTP is exciting. stimulation due to nitric oxide feedback Might there be some way our neurons can mechanisms (Sobczyk & Svoboda, 2007). It direct themselves to learn faster and more was proposed that this decrease in NMDAR efficiently? sensitivity leads to a reduced postsynaptic Certain types of priming stimulation Ca2+ response and thus inhibits LTP (Murphy have indeed been shown to enhance LTP, & Bliss, 1999). As attractive as this though the mechanisms by which this occurs hypothesis is, metaplastic LTP inhibition has appear to be more mysterious and complex been shown to occur independently of this than LTP inhibition. The lowering of the LTP NMDAR-specific desensitization (Moody, threshold, decreasing the amount of Carlisle, & O’Dell, 1999). Although it may be stimulation needed in order to elicit LTP important in NMDAR function, this pathway response, appears not to be based on cannot be directly mediating NMDAR- NMDARs but on an entirely different type of dependent metaplasticity. receptor, the metabotropic glutamine The most promising explanation for receptor. NMDAR-dependent metaplasticity is the In addition to fast-acting ionotropic long-term alteration of the regulatory receptors, there also exists a different class enzyme CaMKII by previous synaptic of receptors that are slower acting, with 'priming' (Bear, 1995). Manipulation of profoundly different structure and effects. CaMKII phosphorylation sites has been These receptors, known as metabotropic or shown to replicate the effect of NMDAR G-protein coupled receptors, do not open priming and increases the amount of ion channels in response to postsynaptic activity needed to induce LTP neurotransmitter binding but instead without any prior high-frequency stimulation activate secondary messenger proteins on

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BNS METAPLASTICITY Literature Review the inside of the postsynaptic membrane. changes on synaptic plasticity. For instance, These secondary messengers can then effect environmentally induced changes in gene long-term changes within the cell, such as expression (epigenetics) have been shown to influencing gene expression and protein be associated with increased LTP during translation (Simon, 2007). learning tasks. Histone acetylation is an Metabotropic glutamate receptors epigenetic process by which certain (mGluRs) appear alongside NMDA and stretches of DNA are made more accessible AMPA receptors in the postsynaptic to transcription proteins, leading to the membrane and are involved in LTP increased production of the proteins facilitation (Cohen & Abraham, 1996). The encoded therein. High levels of histone activation of mGluRs has been shown to acetylation have been found in relevant both facilitate the induction of LTP and brain regions during learning tasks in rats, lengthen its persistence (Bortolotto, Bashir, and experimental manipulation of this Davies, & Collingridge, 1994; Bortolotto et acetylation was shown to affect plasticity al., 1995). This enhancing effect can last up thresholds (Levenson et al., 2004). This not to an hour and appears to be related to the only implicates epigenetics as yet another down-regulating effect that mGluR possible mechanism of metaplasticity, but activation has on the After- also suggests that a learning event in one Hyperpolarization Period (AHP): the length synapse could promote LTP to other of time neurons take to return to their synapses throughout the neuron. By resting potential after firing. A decrease in increasing the availability of proteins the AHP could lead to an increase in whole- involved in late-phase LTP, epigenetics could cell neuronal excitability and an increase in provide a fertile environment for LTP to postsynaptic depolarization due to back- occur and thereby enhance learning. propagation of action potentials from the cell body (Saar, Grossman, & Barkai, 1998). BDNF. The protein known as Brain-Derived- Additionally, mGluR activity may also Neurotrophic-Factor (BDNF) has recently enhance LTP by trafficking AMPARs to the been suggested to be involved in synaptic membrane, preparing them for metaplasticity, although it is uncertain involvement in subsequent plasticity events whether it can effect metaplastic changes its (Oh, Derkach, Guire, & Soderling, 2006). own, or whether it is simply a necessary Despite these promising findings, the factor in LTP induction. BDNF's primary role involvement of mGLuRs in metaplastictic in the brain is developmental: it is involved events has proven difficult to completely in the promotion of neural cell survival, describe. For instance, mGluR activation differentiation, and the establishment and appears to have an inhibitory effect on LTP maintenance of newly formed synapses in the dentate gyrus, and it is unknown how (Huang & Reichardt, 2001). Because of its this effect could be reconciled with their stimulatory effect on most neuronal usual role in enhancing LTP (Gisabella, processes, it is not surprising that artificial Rowan, & Anwyl, 2003). introduction of BDNF can induce LTP (Ying et al., 2002). However, research has revealed Epigenetics. In addition to synaptic receptor that BDNF may also alter the plasticity activity, there are a number of other factors threshold in conjunction with PKMζ, another that can effect long-term modulatory critical protein for LTP induction (Sajikumar

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& Korte, 2011). Furthermore, BDNF appears different task in which the same neurons to be upregulated during certain learning were involved. This suggests that mGluR- tasks (Naimark et al., 2007). BDNF's role in mediated metaplasticity may act as a synaptic plasticity is far from being 'learning switch', providing an improved completely understood and the persistence cellular environment for learning to occur of its effect on LTP induction has yet to be (Zelcer et al., 2006). Similar learning-related demonstrated. Metaplasticity entails a reductions in AHP have also been observed temporal component where synaptic events in reflexive eye-blink conditioning and water at one point in time affect later synaptic maze tasks (Lebel, Grossman, & Barkai, plasticity; this property has yet to be 2001; Moyer, Thompson, & Disterhoft, demonstrated with BDNF, though its 1996). presence does appears to amplify LTP. Within the limited body of behavioural Nevertheless, it does provide a promising research on metaplasticity, an important avenue of research and serves to illustrate observation has arisen which calls into just how many different factors are involved question the accuracy of the BCM model and in regulating synaptic plasticity. previous conceptions about synaptic plasticity regulation. The presence of Metaplasticity and Learning multiple mechanism of metaplasticity Metaplasticity is critical for maintaining (NMDARs, mGluRs), often leads to a failure synaptic plasticity within a dynamic range, of a single sliding threshold model to predict but could it have a more direct role in or explain changes in synaptic plasticity. For learning? Research on the link between example, when decreases in the AHP are metaplasticity and learning is still in its observed, there is almost always a infancy, yet what has been found is exciting simultaneous reduction in LTP as well. This and seems to implicate metaplasticity in suggests that NMDAR-mediated LTP both the facilitation and inhibition of inhibition may occur in dynamic balance learning. For example, it is well known that with mGluR sensitization and illustrates an stress can impair learning, and now research important point: these processes are by no has demonstrated that NMDAR-related means exclusive. With multiple metaplastic metaplasticity triggered by stressful events processes occurring simultaneously, it is may be the reason why (Sacchetti et al., challenging to develop a single model of 2002). Metaplasticity may also increase metaplasticity that is accurate in all neural plasticity during learning periods, situations. At this point, there is no unifying leading to more efficient learning. An explanation for how these different exciting study demonstrated that during mechanisms work together. They may be olfactory-discrimination training in mice, the cooperating, competing, or involved in some AHP period of pyramidal neurons in the complex memory encoding process we have hippocampus was significantly decreased, yet to discover. Explaining the interactions suggesting the presence of mGluR-mediated between discrete metaplastic mechanisms is metaplastic LTP facilitation. Importantly, this a critical question — how do all these pieces effect was present during the learning of the puzzle fit together? period but disappeared once the learning rule had been acquired, and was even correlated with enhanced ability to learn a

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Conclusion Metaplasticity, the modulation of synaptic Declaration of Conflicting Interests plasticity based on previous firing history, is The author declared they have no conflicts critical for the emergence of learning and of interests with respect to their authorship memory. Like memory itself, metaplasticity or the publication of this article. appears to be composed of many different complex processes working together. References NMDAR-mediated metaplasticity inhibits Abraham, W. C., & Bear, M. F. (1996). Metaplasticity: the plasticity of synaptic plasticity. Trends in future LTP through CaMKII phosphorylation Neurosciences, 19(4), 126-130. while mGluR-mediated metaplasticity doi:10.1016/S0166-2236(96)80018-X facilitates LTP via AHP downregulation. Abraham, W. C., Logan, B., Greenwood, J. M., & Histone acetylation enhances LTP by Dragunow, M. (2002). Induction and experience-dependent consolidation of stable increasing transcription of synaptic proteins long-term potentiation lasting months in the and BDNF may play a role in metaplasticity hippocampus. The Journal of Neuroscience, as well. Together, these processes allow 22(21), 9626–9634. neurons to maintain synaptic plasticity Abraham, W. C. (2008). Metaplasticity: tuning synapses and networks for plasticity. Nature within a dynamic range. There is also Reviews Neuroscience, 9(5), 387–387. mounting evidence that metaplasticity is doi:10.1038/nrn2356 involved directly in learning processes Bear, M F. (1995). Mechanism for a sliding synaptic modification threshold. Neuron, 15(1), 1-4. through up-regulation of neural plasticity in Bienenstock, E. L., Cooper, L. N., & Munro, P. W. task-relevant neurons and that a dynamic (1982). Theory for the development of neuron balance between mechanisms may exist in selectivity: orientation specificity and binocular order to regulate these 'learning modes'. interaction in visual cortex. The Journal of Neuroscience: The Official Journal of the Further research on metaplasticity could Society for Neuroscience, 2(1), 32-48. elaborate on this involvement in learning, Blais, B., & Cooper, L. (2008). BCM theory. leading to new discoveries about how we Scholarpedia, 3(3), 1570. learn and providing knowledge to fill the doi:10.4249/scholarpedia.1570 Bortolotto, Z. A., Bashir, Z. I., Davies, C. H., & considerable gap between psychological and Collingridge, G. L. (1994). A molecular switch neurobiological understanding of memory. activated by metabotropic glutamate receptors Although the stated goal of this review regulates induction of long-term potentiation. Nature, 368(6473), 740-743. was to dissect metaplasticity into a simple, doi:10.1038/368740a0 unified, understandable phenomenon, it is Bortolotto, Z. A., Bashir, Z. I., Davies, C. H., Taira, T., clear that metaplasticity cannot be reduced Kaila, K., & Collingridge, G. L. (1995). to a single process. NMDARs, mGluRs, Studies on the role of metabotropic glutamate receptors in long-term potentiation: some neurotrophins, epigenetics – all these methodological considerations. Journal of factors are involved and inter-related in Neuroscience Methods, 59(1), 19-24. ways we do not yet understand, forming a Castillo, P. E. (2012). Presynaptic LTP and LTD of excitatory and inhibitory synapses. Cold Spring very complex phenomenon which is only Harbor Perspectives in Biology, 4(2). superficially cohesive. These phenomena are doi:10.1101/cshperspect.a005728 not neat, orderly, or amenable to a unified Christie, B. R., & Abraham, W. C. (1992). Priming of label. Instead, they constitute a complex associative long-term depression in the dentate gyrus by theta frequency synaptic activity. adaptation to endow organisms with the Neuron, 9(1), 79-84. flexibility to adapt in a chaotic and Coan, E. J., Irving, A. J., & Collingridge, G. L. (1989). unplanned world. Low-frequency activation of the NMDA

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BNS METAPLASTICITY Literature Review

neurotrophic factor (BDNF) and protein kinase synthesis. The Journal of Neuroscience: The Mζ (PKMζ). Proceedings of the National Official Journal of the Society for Academy of Sciences, 108(6), 2551–2556. Neuroscience, 22(5), 1532–1540. doi:10.1073/pnas.1016849108 Zelcer, I., Cohen, H., Richter-Levin, G., Lebiosn, T., Simon, P. (2007). The role of glutamate in central Grossberger, T., & Barkai, E. (2006). A cellular nervous system health and disease – A review. correlate of learning-induced metaplasticity in The Veterinary Journal, 173(2), 278-286. the hippocampus. Cerebral Cortex (New York, doi:10.1016/j.tvjl.2005.11.007 N.Y.: 1991), 16(4), 460-468. Sobczyk, A., & Svoboda, K. (2007). Activity- doi:10.1093/cercor/bhi125 dependent plasticity of the NMDA-receptor Zhang, L., Kirschstein, T., Sommersberg, B., fractional Ca2+ current. Neuron, 53(1), 17-24. Merkens, M., Manahan-Vaughan, D., doi:10.1016/j.neuron.2006.11.016 Elgersma, Y., & Beck, H. (2005). Hippocampal Ying, S.-W., Futter, M., Rosenblum, K., Webber, M. synaptic metaplasticity requires inhibitory J., Hunt, S. P., Bliss, T. V. P., & Bramham, C. autophosphorylation of Ca2+/calmodulin- R. (2002). Brain-derived neurotrophic factor dependent kinase II. The Journal of induces long-term potentiation in intact adult Neuroscience, 25(33), 7697 -7707. hippocampus: requirement for ERK activation doi:10.1523/JNEUROSCI.2086-05.200 coupled to CREB and upregulation of Arc

UBCUJP – In Press – Volume 1