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]

BNS Morrison Literature Review

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

UBCUJP – In Press – Volume 1

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

UBCUJP – In Press – Volume 1

BNS Morrison Literature Review

cascade of secondary messengers travel to described here and despite being an area of the cell nucleus, initiating gene expression active research, is beyond the scope of this and protein synthesis, facilitating increased article. For further detail on LTD production of AMPAR proteins and other mechanisms, readers should consult synaptic proteins (Lynch, 2004). Late-phase Collingridge (2010). LTP often results in an increased postsynaptic surface area and a greater The BCM Theory: Thresholds of number of synaptic vesicles, which further Plasticity amplifies the ability of the presynaptic In order to describe how metaplasticity neuron to excite the postsynaptic neuron affects the induction of synaptic plasticity, it (Desmond & Levy, 1988). Both early- and is appropriate to first address the BCM late-phase LTP are implicated in learning and theory of plasticity thresholds. During memory by enhancing retention of a task for synaptic firing, increases in postsynaptic Ca2+ the first few minutes after it is learned while cause changes in synaptic efficacy: but if Ca2+ also making arrangements for the persistent is the stimulus for both LTP and LTD, then retention of that learning. what determines whether LTP or LTD will be Long-term depression, the weakening induced? Because the effect of Ca2+ is of synaptic efficacy following prolonged low- concentration-dependent, there seems to be frequency stimulation, has not been studied a threshold concentration that determines as extensively as LTP, but its basic mechanics whether potentiation, depression, or no appear similar. During low-frequency change in synaptic efficacy will occur. The stimulation, there is a relatively low degree Bienenstock-Cooper-Munro (BCM) model of postsynaptic depolarization and thus a best characterizes this threshold. much smaller amount of NMDAR activation The BCM model describes a relationship and Ca2+ influx. Interestingly, rather than between postsynaptic response (x-axis on simply leading to a reduced degree of LTP, figure) and change in postsynaptic strength low levels of Ca2+ appear to have the (Φ) with two key features. First, a threshold opposite effect entirely. While high levels of exists (θM) above which the synapse will be Ca2+ phosphorylate regulatory kinases, low strengthened (LTP), and below which it will Ca2+ levels promote their be weakened (LTD). Second, this threshold is dephosphorylation. This leads to a decrease not static, but shifts in response to the in synaptic efficacy via AMPAR average frequency of presynaptic desensitization and removal (Malenka & stimulation (Bienenstock, Cooper, & Munro, Bear, 2004). The selective weakening of 1982). In this way, an increase in sensitivity synapses through LTD is believed to be following LTP induction will not cause even important for the constructive use of LTP. more LTP in a cycle of positive feedback and Indeed, if synapses continued to increase in lead to excitotoxicity (cellular toxicity strength, they would ultimately reach a involving overactivation of glutamate ceiling level of synaptic efficacy which would receptors), and a loss of meaningful input prevent the encoding of new information It from the synapse. A sliding threshold allows is important to note that the complete synaptic plasticity to function as a synaptic picture of these mechanisms, including the 'novelty detector', with the threshold being involvement of other supplementary equal to the average level of activity so that mechanisms, is much more complex than LTP and LTD are only induced during

UBCUJP – In Press – Volume 1

BNS METAPLASTICITY Literature Review significant bursts of in stimulation This effect was dubbed “metaplasticity” frequency. because of its higher-order 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 the same pathway (Huang, Colino, Selig, & higher-order, 'meta', nature of this effect is Malenka, 1992). This effect lasted for exciting not only because of its importance upwards of thirty minutes, was dependent to organized functioning of plasticity, but on NMDAR activation, and seemed to also because it suggests that neurons retain represent a shift in the BCM plasticity a trace of their own activity. threshold since the inhibition could be overcome eventually by increasing the Mechanisms of Metaplasticity intensity of stimulation. These experiments were the first to demonstrate that 'priming' NMDAR: LTP Inhibition. Much like synaptic stimuli, whether it induces LTP or not, can plasticity itself, metaplasticity can either cause covert changes in the synapse which have potentiating or depressing effects. As will affect subsequent plasticity responses. described by the BCM model, a decrease in

UBCUJP – In Press – Volume 1

BNS Morrison Literature Review

successive LTP 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 (Zhang et al., 2005). This is plausible since the inside of the postsynaptic membrane. CaMKII is crucial in both early- and late- These secondary messengers can then effect phase LTP; however, it is unclear whether long-term changes within the cell, such as the activation of CaMKII during influencing gene expression and protein metaplasticity is involved or conflicts with its translation (Simon, 2007). transient phosphorylation during LTP Metabotropic glutamate receptors induction. Recent electrostatic imaging (mGluRs) appear alongside NMDA and studies have revealed that CaMKII is an AMPA receptors in the postsynaptic impressively complex enzyme possessing membrane and are involved in LTP two sets of six binding domains, so it is quite facilitation (Cohen & Abraham, 1996). The possible that it may be activated at multiple activation of mGluRs has been shown to sites independently (Craddock, Tuszynski, & both facilitate the induction of LTP and Hameroff, 2012). This is a fascinating area lengthen its persistence (Bortolotto, Bashir,

UBCUJP – In Press – Volume 1

BNS METAPLASTICITY Literature Review

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 changes on synaptic plasticity. For instance, & Korte, 2011). Furthermore, BDNF appears environmentally induced changes in gene to be upregulated during certain learning expression (epigenetics) have been shown to tasks (Naimark et al., 2007). BDNF's role in be associated with increased LTP during synaptic plasticity is far from being learning tasks. Histone acetylation is an completely understood and the persistence epigenetic process by which certain of its effect on LTP induction has yet to be stretches of DNA are made more accessible demonstrated. Metaplasticity entails a to transcription proteins, leading to the temporal component where synaptic events increased production of the proteins at one point in time affect later synaptic encoded therein. High levels of histone plasticity; this property has yet to be acetylation have been found in relevant demonstrated with BDNF, though its brain regions during learning tasks in rats, presence does appears to amplify LTP. and experimental manipulation of this Nevertheless, it does provide a promising

UBCUJP – In Press – Volume 1

BNS Morrison Literature Review

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 Conclusion correlated with enhanced ability to learn a Metaplasticity, the modulation of synaptic different task in which the same neurons plasticity based on previous firing history, is were involved. This suggests that mGluR- critical for the emergence of learning and mediated metaplasticity may act as a memory. Like memory itself, metaplasticity 'learning switch', providing an improved appears to be composed of many different cellular environment for learning to occur complex processes working together. (Zelcer et al., 2006). Similar learning-related NMDAR-mediated metaplasticity inhibits reductions in AHP have also been observed future LTP through CaMKII phosphorylation in reflexive eye-blink conditioning and water while mGluR-mediated metaplasticity maze tasks (Lebel, Grossman, & Barkai, facilitates LTP via AHP downregulation. 2001; Moyer, Thompson, & Disterhoft, Histone acetylation enhances LTP by 1996). increasing transcription of synaptic proteins Within the limited body of behavioural and BDNF may play a role in metaplasticity research on metaplasticity, an important as well. Together, these processes allow

UBCUJP – In Press – Volume 1

BNS METAPLASTICITY Literature Review 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 through up-regulation of neural plasticity in modification threshold. Neuron, 15(1), 1-4. 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 Further research on metaplasticity could Neuroscience: The Official Journal of the 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. was to dissect metaplasticity into a simple, Nature, 368(6473), 740-743. 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 neurotrophins, epigenetics – all these receptors in long-term potentiation: some 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 very complex phenomenon which is only excitatory and inhibitory synapses. Cold Spring 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 adaptation to endow organisms with the gyrus by theta frequency synaptic activity. 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 receptor system can prevent the induction of Declaration of Conflicting Interests LTP. Neuroscience Letters, 105(1-2), 205–210. Cohen, A. S., & Abraham, W. C. (1996). Facilitation The author declared they have no conflicts of long-term potentiation by prior activation of of interests with respect to their authorship metabotropic glutamate receptors. Journal of or the publication of this article. Neurophysiology, 76(2), 953-962. Collingridge, G. L., Peineau, S., Howland, J. G., & Wang, Y. T. (2010). Long-term depression in References the CNS. Nature Reviews Neuroscience, 11(7), Abraham, W. C., & Bear, M. F. (1996). Metaplasticity: 459–473. doi:10.1038/nrn2867 the plasticity of synaptic plasticity. Trends in Craddock, T. J. A., Tuszynski, J. A., & Hameroff, S. Neurosciences, 19(4), 126-130. (2012). Cytoskeletal Signaling: Is Memory doi:10.1016/S0166-2236(96)80018-X Encoded in Microtubule Lattices by CaMKII Abraham, W. C., Logan, B., Greenwood, J. M., & Phosphorylation? (G. Bernroider, Ed.)PLoS Dragunow, M. (2002). Induction and Computational Biology, 8(3), e1002421. experience-dependent consolidation of stable doi:10.1371/journal.pcbi.1002421 long-term potentiation lasting months in the Desmond, N. L., & Levy, W. B. (1988). Synaptic hippocampus. The Journal of Neuroscience, interface surface area increases with long-term 22(21), 9626–9634. potentiation in the hippocampal dentate gyrus.

UBCUJP – In Press – Volume 1

BNS Morrison Literature Review

Brain Research, 453(1-2), 308-314. Murphy, K. P., Williams, J. H., Bettache, N., & Bliss, Diamond, D. M., Fleshner, M., & Rose, G. M. (1994). T. V. (1994). Photolytic release of nitric oxide Psychological stress repeatedly blocks modulates NMDA receptor-mediated hippocampal primed burst potentiation in transmission but does not induce long-term behaving rats. Behavioural Brain Research, potentiation at hippocampal synapses. 62(1), 1-9. doi:10.1016/0166-4328(94)90032-9 Neuropharmacology, 33(11), 1375-1385. Gisabella, B., Rowan, M. J., & Anwyl, R. (2003). Naimark, A., Barkai, E., Matar, M. A., Kaplan, Z., Mechanisms underlying the inhibition of long- Kozlovsky, N., & Cohen, H. (2007). term potentiation by preconditioning Upregulation of neurotrophic factors stimulation in the hippocampus in vitro. selectively in frontal cortex in response to Neuroscience, 121(2), 297–305. olfactory discrimination learning. Neural Huang, E. J., & Reichardt, L. F. (2001). Plasticity, 2007, 13427. Neurotrophins: roles in neuronal development doi:10.1155/2007/13427 and function. Annual review of neuroscience, Oh, M. C., Derkach, V. A., Guire, E. S., & Soderling, 24, 677–736. T. R. (2006). Extrasynaptic membrane doi:10.1146/annurev.neuro.24.1.677 trafficking regulated by GluR1 serine 845 Huang, Y., Colino, A., Selig, D., & Malenka, R. phosphorylation primes AMPA receptors for (1992). The influence of prior synaptic activity long-term potentiation. Journal of Biological on the induction of long-term potentiation. Chemistry, 281(2), 752 –758. Science, 255(5045), 730 -733. doi:10.1074/jbc.M509677200 doi:10.1126/science.1346729 Pinel, J. P. J. (2007). Biopsychology Eighth Edition. Lebel, D., Grossman, Y., & Barkai, E. (2001). Allyn and Bacon: Toronto Olfactory learning modifies predisposition for Saar, D., Grossman, Y., & Barkai, E. (1998). Reduced long-term potentiation and long-term after-hyperpolarization in rat piriform cortex depression induction in the rat piriform pyramidal neurons is associated with increased (olfactory) rtex. Cerebral Cortex, 11(6), 485– learning capability during operant conditioning. 489. doi:10.1093/cercor/11.6.485 The European Journal of Neuroscience, 10(4), Levenson, J. M., O’Riordan, K. J., Brown, K. D., 1518–1523. Trinh, M. A., Molfese, D. L., & Sweatt, J. D. Sacchetti, B., Lorenzini, C. A., Baldi, E., Bucherelli, (2004). Regulation of histone acetylation C., Roberto, M., Tassoni, G., & Brunelli, M. during memory formation in the hippocampus. (2002). Time-dependent inhibition of Journal of Biological Chemistry, 279(39), hippocampal LTP in vitro following contextual 40545 -40559. doi:10.1074/jbc.M402229200 fear conditioning in the rat. The European Lynch, M. A. (2004). Long-term potentiation and Journal of Neuroscience, 15(1), 143–150. memory. Physiological Reviews, 84(1), 87 - Sajikumar, S., & Korte, M. (2011). Metaplasticity 136. doi:10.1152/physrev.00014.2003 governs compartmentalization of synaptic Malenka, R. C., & Bear, M. F. (2004). LTP and LTD: tagging and capture through brain-derived an embarrassment of riches. Neuron, 44(1), 5- neurotrophic factor (BDNF) and protein kinase 21. doi:10.1016/j.neuron.2004.09.012 Mζ (PKMζ). Proceedings of the National Martin, S. J., Grimwood, P. D., & Morris, R. G. Academy of Sciences, 108(6), 2551–2556. (2000). Synaptic plasticity and memory: an doi:10.1073/pnas.1016849108 evaluation of the hypothesis. Annual Review of Simon, P. (2007). The role of glutamate in central Neuroscience, 23, 649-711. nervous system health and disease – A review. doi:10.1146/annurev.neuro.23.1.649 The Veterinary Journal, 173(2), 278-286. Moody, T. D., Carlisle, H. J., & O’Dell, T. J. (1999). A doi:10.1016/j.tvjl.2005.11.007 Nitric Oxide-Independent and β-Adrenergic Sobczyk, A., & Svoboda, K. (2007). Activity- Receptor-Sensitive Form of Metaplasticity dependent plasticity of the NMDA-receptor Limits θ-Frequency Stimulation-Induced LTP fractional Ca2+ current. Neuron, 53(1), 17-24. in the Hippocampal CA1 Region. Learning & doi:10.1016/j.neuron.2006.11.016 Memory, 6(6), 619–633. Murphy, K. P., & Bliss, T. V. (1999). Photolytically released nitric oxide produces a delayed but persistent suppression of LTP in area CA1 of the rat hippocampal slice. The Journal of Physiology, 515 ( Pt 2), 453–462.

UBCUJP – In Press – Volume 1

BNS METAPLASTICITY Literature Review

Ying, S.-W., Futter, M., Rosenblum, K., Webber, M. the hippocampus. Cerebral Cortex (New York, J., Hunt, S. P., Bliss, T. V. P., & Bramham, C. N.Y.: 1991), 16(4), 460-468. R. (2002). Brain-derived neurotrophic factor doi:10.1093/cercor/bhi125 induces long-term potentiation in intact adult Zhang, L., Kirschstein, T., Sommersberg, B., hippocampus: requirement for ERK activation Merkens, M., Manahan-Vaughan, D., coupled to CREB and upregulation of Arc Elgersma, Y., & Beck, H. (2005). Hippocampal synthesis. The Journal of Neuroscience: The synaptic metaplasticity requires inhibitory Official Journal of the Society for autophosphorylation of Ca2+/calmodulin- Neuroscience, 22(5), 1532–1540. dependent kinase II. The Journal of Zelcer, I., Cohen, H., Richter-Levin, G., Lebiosn, T., Neuroscience, 25(33), 7697 -7707. Grossberger, T., & Barkai, E. (2006). A cellular doi:10.1523/JNEUROSCI.2086-05.200 correlate of learning-induced metaplasticity in

UBCUJP – In Press – Volume 1