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Mitogen-activated protein kinases in synaptic plasticity and memory
Mitogen-activated protein kinases in synaptic plasticity and memory J David Sweatt This review highlights five areas of recent discovery concerning the role of extracellular-signal regulated kinases (ERKs) in the hippocampus. First, ERKs have recently been directly implicated in human learning through studies of a human mental retardation syndrome. Second, new models are being formulated for how ERKs contribute to molecular information processing in dendrites. Third, a role of ERKs in stabilizing structural changes in dendritic spines has been defined. Fourth, a crucial role for ERKs in regulating local dendritic protein synthesis is emerging. Fifth, the importance of ERK interactions with scaffolding and structural proteins at the synapse is increasingly apparent. These topics are discussed within the context of an emerging role for ERKs in a wide variety of forms of synaptic plasticity and memory formation in the behaving animal. Addresses Division of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030-3498, USA e-mail: [email protected]
In this review I focus on the role of signal transduction mechanisms in synaptic plasticity and memory formation. By-and-large I discuss the involvement of these processes in hippocampal function because the hippocampus is involved in the highest-order forms of memory: declarative, episodic, and spatial memory. These higher-order aspects of memory function in cognition are the processes many of us are most interested in ultimately understanding. An additional reason to focus on the hippocampus is that there are behavioral assays to assess hippocampusdependent learning and memory in rodents, which combined with the phenomenal recent progress in genetic engineering techniques has allowed for amazing progress in understanding the molecular basis of hippocampusdependent cognitive processing. Equally as importantly, the rodent hippocampal slice preparation allows the study of use-dependent, long-lasting forms of synaptic plasticity such as long-term potentiation (LTP), which provides us with an in vitro system for studying the role of signal transduction mechanisms in the context of lasting alterations of synaptic function.
Current Opinion in Neurobiology 2004, 14:311–317 This review comes from a themed issue on Signalling mechanisms Edited by Richard L Huganir and S Lawrence Zipursky Available online 22th April 2004 0959-4388/$ – see front matter ß 2004 Elsevier Ltd. All rights reserved. DOI 10.1016/j.conb.2004.04.001 Abbreviations ACh acetylcholine AMPA a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid b-AP back propagating action potential CNS central nervous system ERK extracellular-signal regulated kinase LTP long-term potentiation MAPK mitogen-activated protein kinase NE norepinephrine NF1 neurofibromatosis type 1 NMDA N-methyl-D-aspartate PKC protein kinase C
Introduction Signal transduction mechanisms are integral components of the neuronal information processing machinery. Signaling through cellular protein kinase cascades impinges upon targets at the neuronal membrane, in the cytoplasm, and within the nucleus in order to effect changes in synaptic function and connectivity. www.sciencedirect.com
Progress in this area during the past few years has revealed some surprises about the role of signal transduction mechanisms in hippocampal synaptic plasticity and memory formation. First and foremost is the extraordinary complexity of biochemical signaling that is involved in triggering LTP and the formation of long-term memories [1]. Numerous signaling systems including the cAMP cascade, calcium/calmodulin dependent kinases, nitric oxide/cGMP/cyclic GMP-dependent protein kinase (PKG), protein kinase C (PKC), redox modulation, growth factor receptor tyrosine kinases, rho/rac signaling, cell adhesion molecules, and the mitogen-activated protein kinases (MAPKs) all have been implicated as playing crucial parts in hippocampal synaptic plasticity and hippocampus-dependent memory formation. Moreover, it is now clear that there is substantial interplay between and among these signaling pathways, increasing the level of complexity and implying a great degree of integration and coordination for signal transduction in hippocampal LTP induction. Although this degree of complexity was unanticipated 20 years ago, it now appears that complexity of cellular signaling could be the rule rather than the exception for plasticity at both adult and developing synapses. In retrospect, this is perhaps not surprising because signal transduction cascades are in essence biochemical information processing systems, and great sophistication at this level is necessary for neurons and synapses to appropriately compute whether or not to trigger a long-lasting change in their function. Current Opinion in Neurobiology 2004, 14:311–317
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Against this backdrop, for a short review such as this it is necessary to focus on only a few specific aspects of signal transduction mechanisms in plasticity and memory. For this review I have chosen to focus on the extracellularsignal regulated kinase (ERK) subfamily of MAPKs. In part I chose this cascade because of its novelty in the context of central nervous system (CNS) function — until recently the cascade had largely been investigated for its role in regulating cell division and differentiation in cells outside the CNS. I am also motivated to focus on ERK because a wide variety of recent studies during the past ten years indicate its clear importance in synaptic plasticity and memory formation in general, across many species, brain areas, and types of synapses (see [2–13,14,15,16] for some important recent examples and possible exceptions to this generalization). Finally, very exciting recent data have directly implicated dysregulation of ERK as a mechanism for a learning disorder in humans; neurofibromatosis-1 associated mental retardation. The format of the review is as follows. In the first section I highlight what I consider to be two particularly exciting recent developments in the area of ERK function in plasticity and cognition. Space limitations do not allow
me to give just treatment to these topics, but at least I am able to draw these areas to your attention, and hopefully prompt further reading of the primary literature. In the second section I speculate briefly on what I consider to be areas of future investigation ripe for discovery. Ideally this will prompt young investigators interested in this area to pursue these topics for their research projects. Regardless, those investigators (young and old) working on the five ‘hot topics’ discussed in this review might take some pleasure from the fact that their work is making considerable impact (see Figures 1 and 2).
A role for the ras/extracellular-signal regulated kinase cascade in human cognition Some of the most exciting recent work in this area has been a series of studies implicating the ras/ERK cascade in human learning. Silva and his co-workers [17–19,20] have for several years been studying neurofibromatosis type 1 (NF1) — associated mental retardation. Capitalizing on the identification of the NF1 gene, they were able to take a sophisticated molecular genetics approach using genetically engineered mouse models [17,19] to determine one basis for the learning deficits associated with
Figure 1
NMDA receptors?
? Scaffolding proteins, ras GRF
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Regulation and targets of the ras/ERK pathway in neurons. The ERK/MAP kinase cascade can be activated by a number of receptors and protein kinases within the hippocampus. As such, it can integrate a wide variety of signals and result in a final common output. The ERK cascade is initiated by the activation of Raf kinase through the small GTP-binding protein, ras, or the ras-related protein, rap-1. Activated Raf then phosphorylates MEK (mitogen extracellular regulating kinase), a dual specific kinase. MEK phosphorylates ERK 1 and 2 on a tyrosine and threonine residue. Once activated, ERK exerts many downstream effects, including the regulation of cellular excitability and the activation of transcription factors leading to altered gene expression. Each MAP kinase cascade (ERK, JNK, and p38 MAPK) is composed of three distinct kinases activated in sequence, and despite the fact that many separate MAP kinase families exist, there is limited crosstalk between these highly homologous cascades. Although many of the steps of the ERK cascade have been elucidated, the mechanisms by which the components of the MAP kinase cascade come into physical contact have not been investigated. In this context it is interesting to note that there are multiple upstream regulators of ERK in the hippocampus: NE, DA, nicotinic ACh, muscarinic ACh, histamine, estrogen, serotonin, brain derived neurotrophic factor (BDNF), NMDA receptors, metabotropic glutamate receptors, AMPA receptors, voltage-gated calcium channels, reactive oxygen species, various PKC isoforms, PKA, nitric oxide (NO), NF1, and multiple ras isoforms and homologs. Current Opinion in Neurobiology 2004, 14:311–317
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Figure 2
neurofibromatosis, specifically disruption of ras/ERK signaling in the hippocampus [20]. CA1 neuron
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A model for ERK regulation of dendritic potassium channels. An emerging hypothesis is that complex b-adrenergic receptor regulation of Kv4.2 contributes to increasing the sophistication of information processing that can be achieved by the hippocampal pyramidal neuron. Specifically, it can allow for 3-way coincidence detection — consider the following example, which is hypothetical at this point but based on a number of recent studies [32,33,34, 35–37]. This example is a combination of the NMDA receptor in its classical role as a detector of coincident membrane depolarization and synaptic glutamate, plus b-adrenergic receptor activation of ERK, and potassium channel regulation by ERK. Imagine that LTP will be triggered by a back-propagating action potential (b-AP), caused in response to a strong action-potential-triggering input at a distal synapse, coupled with local synaptic glutamate. LTP results because the NMDA receptor senses b-AP-associated membrane depolarization coupled with synaptic glutamate at the synapse of interest. In addition, available data indicate that A-type Kþ currents would limit the capacity of the b-AP to reach the synapse and thus depolarize the NMDA receptor, except that a b-adrenergic receptor has activated ERK and down-regulated these channels. Thus, the b-adrenergic receptor has gated the b-AP and allowed it to enter the relevant dendritic region. This allows NMDA receptor activation, and the resulting calcium influx through the NMDA receptor is sufficient to cause robust synaptic LTP. In this example a strong synaptic input at a distal synapse, plus a weak synaptic input, plus one neuromodulatory input (NE), has uniquely triggered lasting synaptic plasticity: 3-way coincidence detection. The model draws directly from data published by Winder and his collaborators [37], O’Dell’s group [36], and us and several of our colleagues [32,33,34,35,50].
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The product of the NF1 gene is neurofibromin, a multidomain molecule that has the capacity to regulate several intracellular processes, including the ERK cascade by serving as a GTPase-activating protein (GAP) for ras. Work from the Silva laboratory demonstrated that some neurofibromatosis-associated NF1 mutations, that is those linked to the mental retardation phenotype, disrupt neurofibromin GAP activity and lead to hyperactivation of ras in the hippocampus. In a sophisticated multidisciplinary series of studies Silva and his co-workers provided compelling evidence that this ras/ERK hyperactivation contributes to hippocampus-dependent learning and memory deficits and disruption of LTP at Schaffer collateral synapses, using their mouse model of neurofibromatosis mental retardation [20]. It is important to note that the basis of these deficits does not appear to be caused by anatomical mis-wiring of the CNS or hippocampus, or to alterations in baseline synaptic connectivity. Rather, the synaptic plasticity and learning deficits are due to dysregulation of signal transduction mechanisms operating in association with acute activitydependent processes of synaptic plasticity. This is just one specific example of an emerging paradigm shift in thinking about human mental retardation. Mental retardation can no longer be thought of as exclusively a developmental problem caused by anatomical derangement, but rather we must now also consider that disruption of ongoing plasticity-related synaptic signal transduction mechanisms will play a part as well [20,21–23]. These recent studies into neurofibromatosis-associated mental retardation have given new insights into the molecular underpinnings of human cognitive processing, in particular to mechanisms likely to contribute to learning and memory. Importantly in the present context, they specifically implicate the hippocampal ras/ERK pathway in human mental retardation and by extension in normal learning and memory as well. What is it that ERK is doing in order to help make synapses plastic and the brain mnemonic? For the remainder of this brief review I focus on a number of interesting new potential roles for ERK in this context. These are in addition to its canonical role as a regulator of gene expression [24–30], which I do not cover here.
Extracellular-signal regulated kinase regulation of potassium channels — dendritic information processing The N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor is the prototype ‘cognitive molecule’ — this receptor has immediate appeal in the context of molecular information processing because it can serve Current Opinion in Neurobiology 2004, 14:311–317
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as a coincidence detector. Thus, the NMDA receptor is selectively opened upon two simultaneous actions: binding of glutamate and depolarization of the membrane in which it resides. One theme that is beginning to emerge from work on dendritic potassium channels in hippocampal pyramidal neurons is that Kþ channels might provide the neuron with additional information processing capacity — they do this through controlling the membrane depolarization that the NMDA receptor senses. Specifically, the emerging model is that voltage-dependent Kþ channels of the Kv4.x family regulate membrane depolarization at the dendritic spine level through controlling local membrane depolarization or through regulating the arrival and/or effects of dendritic back-propagating action potentials (see Birnbaum et al. [31] for a review). Thus, Kþ channels appear to operate as partners of the NMDA receptor, in that they allow a more sophisticated level of information processing by controlling the membrane potential that the NMDA receptor detects. This is especially important because Kþ channels, in particular A-type channels, such as those encoded by Kv4 family members, are themselves subject to modulation. The Kþ channels detect and integrate biochemical signals and provide this mechanism for conferring more sophisticated control over NMDA receptor activation. Important recent work has shown that the modulation of dendritic Kþ channel function by the protein kinase A (PKA) and PKC cascades, or by b-adrenergic receptor activators, is dependent on the activation of ERK [32,33,34,35–37]. The molecular mechanism for this modulation appears to be direct phosphorylation of the pore-forming alpha subunit of Kv4-family potassium channels [32,34,35]. This phosphorylation event is hypothesized to cause an alteration in channel properties such that the voltage-dependence of activation is shifted in a depolarizing direction. In other words, greater depolarization is required to open the potassium channels, increasing membrane excitability. This increase in membrane excitability allows for augmented NMDA receptor activation when the membrane is depolarized by the opening of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, or through a back-propagating action potential (see Figure 2). This mechanism is likely to be particularly important in ‘theta-type’ LTP, that is, 5 Hz-stimulation induced LTP [33,36,37]. Theta frequency stimulation mimics an endogenous CA1 neuron firing pattern that rodents manifest when they are learning about their environment. Theta-frequency stimulation causes action potential bursting in area CA1 cells, which can back-propagate into the dendrites and depolarize synapses. Several groups, including the laboratories of Kandel, Winder, and O’Dell [33,36,37] have shown that blocking ERK activation in mouse area CA1 blocks not only the complex Current Opinion in Neurobiology 2004, 14:311–317
spike bursting seen with the theta-frequency stimulation protocol but also the LTP that is so induced. In addition, Winder and co-workers [37] have found that b-adrenergic receptor-mediated modulation of LTP induced with theta-frequency stimulation is blocked by inhibitors of ERK activation. Again, these findings are consistent with a model in which ERK regulation of membrane electrical properties, through control of Kv4-family channels, regulates back-propagating action potentials and controls NMDA receptor activation. What is the role of this complex b-adrenergic receptor regulation of potassium channels and the NMDA receptor? It may contribute to increasing the sophistication of information processing that can be achieved by the hippocampal pyramidal neuron. Specifically, it can allow for 3-way coincidence detection (Figure 2). Under the conditions described above, synaptic potentiation will be selectively triggered only upon the simultaneous presence of: first, synaptic glutamate, second, a back-propagating action potential, and third, norepinephrine (NE) to inhibit Kþ channels and allow the NMDA receptor to sense the depolarization. Moreover, in hippocampal pyramidal neurons various NE, dopamine (DA), serotonin (5HT), and acetylcholine (ACh) receptor subtypes can also couple to activation of ERK in the hippocampus (see Figure 1). Overall then, this mechanism for 3-way coincidence detection might be utilized as a general and powerful means of enhancing dendritic information processing capacity.
Hot areas in the future? To keep the review brief in the last section I tersely highlight three areas that I think are likely areas of rapid and important advancement in the near future. For each area I present a few recent references to give the flavor of new developments.
Ras/extracellular-signal regulated kinase regulation of dendritic spines ERK has recently been implicated as an important regulator of activity-dependent structural changes in hippocampal neurons [38,39]. Specifically, formation and stabilization of dendritic spines involves ERK activation, a role likely to be involved in long-term information storage in the CNS. In an interesting twist, Wu [38] has found that these effects of ERK require repeated spaced stimulation, indicating that ERK is somehow involved in signal integration over fairly long time periods.
Extracellular-signal regulated kinase regulation of local dendritic protein synthesis It is becoming clear that ERK will be a crucial regulator of protein synthesis in dendrites. This reprises one of the general roles of ERK in non-neuronal cells, in which MAPKs in general are pluripotent regulators of processes www.sciencedirect.com
Mitogen-activated protein kinases in synaptic plasticity and memory Sweatt 315
involved in mitogenic stimulation, that is, preparing the cell for replication. In non-dividing adult neurons, however, the system must have been adapted to more subtle modes of regulation and specificity of targeting, because regulation of protein synthesis has been adapted specifically to activity-dependent processes leading to subtle long-term structural changes (see [40,41], for example). Landau and co-workers [42] have already identified calcium/calmodulin dependent kinase II (CaMKII) as one specific target of ERK-dependent changes in protein synthesis in hippocampal neurons, an effect specifically investigated in the context of LTP-inducing stimulation. In a recent technical tour-de-force, Kelleher, Govindarajan and co-workers [43] have used transgenic approaches and a multidisciplinary investigation to implicate ERK directly as a regulator of protein translation required for LTP and memory formation in vivo.
The interplay of extracellular-signal regulated kinase and synaptic structural proteins One of the important areas of recent advancement in the signal transduction field has been the appreciation of the important part that scaffolding proteins play in coordinating and segregating the actions of specific signaling cascades. This important principle in the area of signal transduction has been paralleled in the neurosciences by the emerging significance of scaffolding proteins in regulating synaptic function. In the context of this review, scaffolding proteins are likely to be particularly important in regulating MAPK cascades at the synapse. For example, MAPKs are regulated by a wide variety of upstream triggers, including different types of receptors, other signaling cascades, and a variety of ras G protein isoforms (see Figure 1). Currently around twenty different neurotransmitter systems or cellular signaling systems are known to regulate ERK in hippocampal neurons. This raises the important question of how the various upstream regulators maintain specificity in their coupling to MAPKs such as ERK. One contemporary hypothesis in this area is that scaffolding proteins compartmentalize specific pools of MAPKs to maintain fidelity of signaling from specific upstream regulators [44,45,46]. The mirror image of this process might also occur, because there are interesting recent findings suggesting that ERK in turn regulates the expression and localization of scaffolding proteins at synapses as well [47,48,49]. One seminal finding in this area of late is the discovery that ras/ERK regulates AMPA receptor trafficking and expression [49]. Overall this appears to be an area that will yield many new insights into the roles and regulation of ERK in neurons.
Conclusions The studies highlighted in this review describe an emerging understanding of the roles of the ERK/MAPK cascade in learning and memory. Studies using several behavioral www.sciencedirect.com
memory paradigms have implicated ERK as an essential component of the signal transduction mechanisms subserving behavioral memory formation. Many studies have implicated ERK as a crucial player in synaptic and neuronal plasticity — a cellular role that is likely to underlie ERK’s behavioral role in the animal. Molecular studies have indicated the complexities of biochemical regulation of ERK in neurons and have highlighted the variety of likely cellular targets of ERK. Understanding these complexities and varieties of targets will be important for understanding the molecular basis of ERK-mediated behavioral change. I speculate that the complexities and idiosyncrasies of ERK regulation might allow for sophisticated information processing at the biochemical level in neurons — attributes that might make the ERK cascade particularly well-suited for triggering complex and long-lasting behavioral change.
Acknowledgements The work in the author’s laboratory is supported by funding from the National Institutes of Health.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest 1.
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11. Selcher JC, Weeber EJ, Christian J, Nekrasova T, Landreth GE, Sweatt JD: A role for ERK MAP kinase in physiologic temporal integration in hippocampal area CA1. Learn Mem 2003, 10:26-39. 12. Sharma SK, Sherff CM, Shobe J, Bagnall MW, Sutton MA, Carew TJ: Differential role of mitogen-activated protein kinase in three distinct phases of memory for sensitization in Aplysia. J Neurosci 2003, 23:3899-3907. 13. Thiels E, Kanterewicz BI, Norman ED, Trzaskos JM, Klann E: Longterm depression in the adult hippocampus in vivo involves activation of extracellular signal-regulated kinase and phosphorylation of Elk-1. J Neurosci 2002, 22:2054-2062. 14. Xiong W, Ferrell JE Jr: A positive-feedback-based bistable ‘memory module’ that governs a cell fate decision. Nature 2003, 426:460-465. This paper describes a novel mechanism by which ERK activation can contribute to long-term information storage. These investigators found that positive feedback activation of ERK is involved in a committed developmental step, using a non-neuronal experimental system. 15. Yasuda H, Barth AL, Stellwagen D, Malenka RC: A developmental switch in the signaling cascades for LTP induction. Nat Neurosci 2003, 6:15-16. These studies demonstrate that all LTP is not equal at the molecular level, even when studied at the same synapse. Thus, these investigators found that the signal transduction mechanisms necessary for LTP induction at immature synapses in culture are different from those involved in LTP at mature synapses. These findings introduce an important caveat to keep in mind when comparing findings using cultured neurons to those obtained using adult tissue. 16. Zhang JJ, Okutani F, Inoue S, Kaba H: Activation of the mitogenactivated protein kinase/extracellular signal-regulated kinase signaling pathway leading to cyclic AMP response elementbinding protein phosphorylation is required for the long-term facilitation process of aversive olfactory learning in young rats. Neuroscience 2003, 121:9-16. 17. Silva AJ, Frankland PW, Marowitz Z, Friedman E, Laszlo GS, Cioffi D, Jacks T, Bourtchuladze R, Lazlo G: A mouse model for the learning and memory deficits associated with neurofibromatosis type I. Nat Genet 1997, 15:281-284. 18. Ohno M, Frankland PW, Chen AP, Costa RM, Silva AJ: Inducible, pharmacogenetic approaches to the study of learning and memory. Nat Neurosci 2001, 4:1238-1243. 19. Costa RM, Yang T, Huynh DP, Pulst SM, Viskochil DH, Silva AJ, Brannan CI: Learning deficits, but normal development and tumor predisposition, in mice lacking exon 23a of Nf1. Nat Genet 2001, 27:399-405. 20. Costa RM, Federov NB, Kogan JH, Murphy GG, Stern J, Ohno M, Kucherlapati R, Jacks T, Silva AJ: Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature 2002, 415:526-530. This landmark paper directly implicates ERK dysregulation in one form of human mental retardation. By extension these studies thereby implicate ERK function in normal human learning as well. 21. Jiang YH, Armstrong D, Albrecht U, Atkins CM, Noebels JL, Eichele G, Sweatt JD, Beaudet AL: Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron 1998, 21:799-811. 22. Weeber EJ, Jiang YH, Elgersma Y, Varga AW, Carrasquillo Y, Brown SE, Christian JM, Mirnikjoo B, Silva A, Beaudet AL et al.: Derangements of hippocampal calcium/calmodulindependent protein kinase II in a mouse model for Angelman mental retardation syndrome. J Neurosci 2003, 23:2634-2644. 23. Zoghbi HY: Postnatal neurodevelopmental disorders: meeting at the synapse? Science 2003, 302:826-830. 24. Impey S, Obrietan K, Wong ST, Poser S, Yano S, Wayman G, Deloulme JC, Chan G, Storm DR: Cross talk between ERK and PKA is required for Ca2R stimulation of CREB-dependent transcription and ERK nuclear translocation. Neuron 1998, 21:869-883. 25. Roberson ED, English JD, Adams JP, Selcher JC, Kondratick C, Sweatt JD: The mitogen-activated protein kinase cascade Current Opinion in Neurobiology 2004, 14:311–317
couples PKA and PKC to cAMP response element binding protein phosphorylation in area CA1 of hippocampus. J Neurosci 1999, 19:4337-4348. 26. Martin KC, Michael D, Rose JC, Barad M, Casadio A, Zhu H, Kandel ER: MAP kinase translocates into the nucleus of the presynaptic cell and is required for long-term facilitation in Aplysia. Neuron 1997, 18:899-912. 27. Impey S, Smith DM, Obrietan K, Donahue R, Wade C, Storm DR: Stimulation of cAMP response element (CRE)-mediated transcription during contextual learning. Nat Neurosci 1998, 1:595-601. 28. Patterson SL, Pittenger C, Morozov A, Martin KC, Scanlin H, Drake C, Kandel ER: Some forms of cAMP-mediated longlasting potentiation are associated with release of BDNF and nuclear translocation of phospho-MAP kinase. Neuron 2001, 32:123-140. 29. Waltereit R, Dammermann B, Wulff P, Scafidi J, Staubli U, Kauselmann G, Bundman M, Kuhl D: Arg3.1/Arc mRNA induction by Ca2R and cAMP requires protein kinase A and mitogenactivated protein kinase/extracellular regulated kinase activation. J Neurosci 2001, 21:5484-5493. 30. Davis S, Vanhoutte P, Pages C, Caboche J, Laroche S: The MAPK/ ERK cascade targets both Elk-1 and cAMP response elementbinding protein to control long-term potentiation-dependent gene expression in the dentate gyrus in vivo. J Neurosci 2000, 20:4563-4572. 31. Birnbaum SG, Varga AW, Yuan L-L, Anderson AE, Sweatt JD, Schrader LA: Structure and function of Kv4-family transient potassium channels. Physiol Rev 2004, In press. 32. Yuan LL, Adams JP, Swank M, Sweatt JD, Johnston D: Protein kinase modulation of dendritic KR channels in hippocampus involves a mitogen-activated protein kinase pathway. J Neurosci 2002, 22:4860-4868. The authors investigated ERK modulation of dendritic A-type Kþ channels in dendrites of CA1 pyramidal neurons. These studies showed that activation of PKA and PKC led to an increase in the amplitude of back-propagating action potentials in distal dendrites through downregulation of transient Kþ channels. Both of these signaling pathways acted through ERK in mediating this reduction in dendritic Kþ current, and biochemical assays using phosphospecific antibodies against ERKphosphorylated Kv4.2 suggested that the modulation of these Kþ channels could be accounted for by the direct phosphorylation of Kv4.2 subunits by ERK. 33. Watanabe S, Hoffman DA, Migliore M, Johnston D: Dendritic KR channels contribute to spike-timing dependent long-term potentiation in hippocampal pyramidal neurons. Proc Natl Acad Sci USA 2002, 99:8366-8371. The authors obtained results from direct patch-clamp recording of hippocampal pyramidal neuron dendrites indicating that ERK activation shifts the voltage-dependent activation of dendritic potassium channels to more depolarized potentials. In other words, dendritic ERK activation appears to suppress potassium channel function and increase membrane excitability. These results support the hypothesis that suppression of dendritic Kþ channels and the resultant boosting of back-propagating action potentials contribute to the induction of NMDA-receptor-dependent LTP in CA1 neurons. 34. Morozov A, Muzzio IA, Bourtchouladze R, Van-Strien N, Lapidus K, Yin D, Winder DG, Adams JP, Sweatt JD, Kandel ER: Rap1 couples cAMP signaling to a distinct pool of p42/44MAPK regulating excitability, synaptic plasticity, learning, and memory. Neuron 2003, 39:309-325. The studies by Yuan et al., Watanabe et al. and Morozov et al. [32–34] demonstrate an important role for ERK in regulating dendritic potassium channels, a role that is likely to contribute to dendritic information processing and the regulation of NMDA receptor activation. The studies by Morozov et al. also implicate these processes in hippocampal LTP and in memory formation in the behaving animal. 35. Adams JP, Anderson AE, Varga AW, Dineley KT, Cook RG, Pfaffinger PJ, Sweatt JD: The A-type potassium channel Kv4.2 is a substrate for the mitogen-activated protein kinase ERK. J Neurochem 2000, 75:2277-2287. 36. Watabe AM, Zaki PA, O’Dell TJ: Coactivation of beta-adrenergic and cholinergic receptors enhances the induction of long-term potentiation and synergistically activates mitogen-activated www.sciencedirect.com
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protein kinase in the hippocampal CA1 region. J Neurosci 2000, 20:5924-5931. 37. Winder DG, Martin KC, Muzzio IA, Rohrer D, Chruscinski A, Kobilka B, Kandel ER: ERK plays a regulatory role in induction of LTP by theta frequency stimulation and its modulation by beta-adrenergic receptors. Neuron 1999, 24:715-726. 38. Wu GY, Deisseroth K, Tsien RW: Spaced stimuli stabilize MAPK pathway activation and its effects on dendritic morphology. Nat Neurosci 2001, 4:151-158. 39. Goldin M, Segal M: Protein kinase C and ERK involvement in dendritic spine plasticity in cultured rodent hippocampal neurons. Eur J Neurosci 2003, 17:2529-2539. The studies by Wu et al. and Goldin and Segal [38,39] highlight a necessity for ERK in stabilizing morphological changes in dendritic spines, a mechanism likely to be relevant to triggering long-lasting changes in neuronal circuit structure. In addition, ERK also can serve as a signal integrator, detecting repeated stimuli delivered over time. 40. Ying SW, Futter M, Rosenblum K, Webber MJ, Hunt SP, Bliss TV, Bramham CR: Brain-derived neurotrophic factor induces longterm potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of Arc synthesis. J Neurosci 2002, 22:1532-1540. 41. Ehlers MD: Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. Nat Neurosci 2003, 6:231-242. 42. Giovannini MG, Blitzer RD, Wong T, Asoma K, Tsokas P, Morrison JH, Iyengar R, Landau EM: Mitogen-activated protein kinase regulates early phosphorylation and delayed expression of Ca2R/calmodulin-dependent protein kinase II in long-term potentiation. J Neurosci 2001, 21:7053-7062. 43. Kelleher RJ, Govindarajan A, Jung HY, Kang H, Tonegawa S: Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell 2004, 116:467-479. The studies by Giovannini et al. and Kelleher et al. [42,43] investigate an emerging new role for ERK in the hippocampus, the regulation of local dendritic protein synthesis. Moreover, these papers directly implicate a necessity for this function of ERK in LTP and memory formation in the behaving animal.
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44. Vanhoose AM, Emery M, Jimenez L, Winder DG: ERK activation by G-protein-coupled receptors in mouse brain is receptor identity-specific. J Biol Chem 2002, 277:9049-9053. 45. Krapivinsky G, Krapivinsky L, Manasian Y, Ivanov A, Tyzio R, Pellegrino C, Ben-Ari Y, Clapham DE, Medina I: The NMDA receptor is coupled to the ERK pathway by a direct interaction between NR2B and RasGRF1. Neuron 2003, 40:775-784. Krapivinsky et al. highlight a new mechanism relevant to ras/ERK signaling, that is scaffolding and structural proteins important in regulating ERK activation. These studies specifically implicate these processes in NMDA receptor coupling to ERK in the hippocampus. 46. Komiyama NH, Watabe AM, Carlisle HJ, Porter K, Charlesworth P, Monti J, Strathdee DJ, O’Carroll CM, Martin SJ, Morris RG et al.: SynGAP regulates ERK/MAPK signaling, synaptic plasticity, and learning in the complex with postsynaptic density 95 and NMDA receptor. J Neurosci 2002, 22:9721-9732. The authors report that the postsynaptic scaffolding protein PSD-95 is one regulator of postsynaptic ras activation, probably involving its interaction with the GTPase activating protein synGAP. Their data also highlight the likelihood of complexity in the interactions of scaffolding and structural proteins with the ras and ERK pathways in neurons. 47. Rosenblum K, Futter M, Voss K, Erent M, Skehel PA, French P, Obosi L, Jones MW, Bliss TV: The role of extracellular regulated kinases I/II in late-phase long-term potentiation. J Neurosci 2002, 22:5432-5441. 48. Kato A, Fukazawa Y, Ozawa F, Inokuchi K, Sugiyama H: Activation of ERK cascade promotes accumulation of Vesl-1S/Homer-1a immunoreactivity at synapses. Brain Res Mol Brain Res 2003, 118:33-44. 49. Zhu JJ, Qin Y, Zhao M, Van Aelst L, Malinow R: Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 2002, 110:443-455. The authors report an important new role for the ras/ERK cascade in the hippocampus — regulating the trafficking and insertion of AMPA receptors. These studies thereby identify an important new target of ras/ERK at central synapses. 50. Hoffman DA, Magee JC, Colbert CM, Johnston D: KR channel regulation of signal propagation in dendrites of hippocampal pyramidal neurons. Nature 1997, 387:869-875.
Current Opinion in Neurobiology 2004, 14:311–317
In this review I focus on the role of signal transduction mechanisms in synaptic plasticity and memory formation. By-and-large I discuss the involvement of these processes in hippocampal function because the hippocampus is involved in the highest-order forms of memory: declarative, episodic, and spatial memory. These higher-order aspects of memory function in cognition are the processes many of us are most interested in ultimately understanding. An additional reason to focus on the hippocampus is that there are behavioral assays to assess hippocampusdependent learning and memory in rodents, which combined with the phenomenal recent progress in genetic engineering techniques has allowed for amazing progress in understanding the molecular basis of hippocampusdependent cognitive processing. Equally as importantly, the rodent hippocampal slice preparation allows the study of use-dependent, long-lasting forms of synaptic plasticity such as long-term potentiation (LTP), which provides us with an in vitro system for studying the role of signal transduction mechanisms in the context of lasting alterations of synaptic function.
Current Opinion in Neurobiology 2004, 14:311–317 This review comes from a themed issue on Signalling mechanisms Edited by Richard L Huganir and S Lawrence Zipursky Available online 22th April 2004 0959-4388/$ – see front matter ß 2004 Elsevier Ltd. All rights reserved. DOI 10.1016/j.conb.2004.04.001 Abbreviations ACh acetylcholine AMPA a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid b-AP back propagating action potential CNS central nervous system ERK extracellular-signal regulated kinase LTP long-term potentiation MAPK mitogen-activated protein kinase NE norepinephrine NF1 neurofibromatosis type 1 NMDA N-methyl-D-aspartate PKC protein kinase C
Introduction Signal transduction mechanisms are integral components of the neuronal information processing machinery. Signaling through cellular protein kinase cascades impinges upon targets at the neuronal membrane, in the cytoplasm, and within the nucleus in order to effect changes in synaptic function and connectivity. www.sciencedirect.com
Progress in this area during the past few years has revealed some surprises about the role of signal transduction mechanisms in hippocampal synaptic plasticity and memory formation. First and foremost is the extraordinary complexity of biochemical signaling that is involved in triggering LTP and the formation of long-term memories [1]. Numerous signaling systems including the cAMP cascade, calcium/calmodulin dependent kinases, nitric oxide/cGMP/cyclic GMP-dependent protein kinase (PKG), protein kinase C (PKC), redox modulation, growth factor receptor tyrosine kinases, rho/rac signaling, cell adhesion molecules, and the mitogen-activated protein kinases (MAPKs) all have been implicated as playing crucial parts in hippocampal synaptic plasticity and hippocampus-dependent memory formation. Moreover, it is now clear that there is substantial interplay between and among these signaling pathways, increasing the level of complexity and implying a great degree of integration and coordination for signal transduction in hippocampal LTP induction. Although this degree of complexity was unanticipated 20 years ago, it now appears that complexity of cellular signaling could be the rule rather than the exception for plasticity at both adult and developing synapses. In retrospect, this is perhaps not surprising because signal transduction cascades are in essence biochemical information processing systems, and great sophistication at this level is necessary for neurons and synapses to appropriately compute whether or not to trigger a long-lasting change in their function. Current Opinion in Neurobiology 2004, 14:311–317
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Against this backdrop, for a short review such as this it is necessary to focus on only a few specific aspects of signal transduction mechanisms in plasticity and memory. For this review I have chosen to focus on the extracellularsignal regulated kinase (ERK) subfamily of MAPKs. In part I chose this cascade because of its novelty in the context of central nervous system (CNS) function — until recently the cascade had largely been investigated for its role in regulating cell division and differentiation in cells outside the CNS. I am also motivated to focus on ERK because a wide variety of recent studies during the past ten years indicate its clear importance in synaptic plasticity and memory formation in general, across many species, brain areas, and types of synapses (see [2–13,14,15,16] for some important recent examples and possible exceptions to this generalization). Finally, very exciting recent data have directly implicated dysregulation of ERK as a mechanism for a learning disorder in humans; neurofibromatosis-1 associated mental retardation. The format of the review is as follows. In the first section I highlight what I consider to be two particularly exciting recent developments in the area of ERK function in plasticity and cognition. Space limitations do not allow
me to give just treatment to these topics, but at least I am able to draw these areas to your attention, and hopefully prompt further reading of the primary literature. In the second section I speculate briefly on what I consider to be areas of future investigation ripe for discovery. Ideally this will prompt young investigators interested in this area to pursue these topics for their research projects. Regardless, those investigators (young and old) working on the five ‘hot topics’ discussed in this review might take some pleasure from the fact that their work is making considerable impact (see Figures 1 and 2).
A role for the ras/extracellular-signal regulated kinase cascade in human cognition Some of the most exciting recent work in this area has been a series of studies implicating the ras/ERK cascade in human learning. Silva and his co-workers [17–19,20] have for several years been studying neurofibromatosis type 1 (NF1) — associated mental retardation. Capitalizing on the identification of the NF1 gene, they were able to take a sophisticated molecular genetics approach using genetically engineered mouse models [17,19] to determine one basis for the learning deficits associated with
Figure 1
NMDA receptors?
? Scaffolding proteins, ras GRF
Receptor tyrosine kinases
PLC-coupled receptors
Adenylyl cyclase coupled receptors
Ras
PKC
PKA
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B-Raf
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Changes in Dendritic spine gene expression stabilization
Modulation of ion channels
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Current Opinion in Neurobiology
Regulation and targets of the ras/ERK pathway in neurons. The ERK/MAP kinase cascade can be activated by a number of receptors and protein kinases within the hippocampus. As such, it can integrate a wide variety of signals and result in a final common output. The ERK cascade is initiated by the activation of Raf kinase through the small GTP-binding protein, ras, or the ras-related protein, rap-1. Activated Raf then phosphorylates MEK (mitogen extracellular regulating kinase), a dual specific kinase. MEK phosphorylates ERK 1 and 2 on a tyrosine and threonine residue. Once activated, ERK exerts many downstream effects, including the regulation of cellular excitability and the activation of transcription factors leading to altered gene expression. Each MAP kinase cascade (ERK, JNK, and p38 MAPK) is composed of three distinct kinases activated in sequence, and despite the fact that many separate MAP kinase families exist, there is limited crosstalk between these highly homologous cascades. Although many of the steps of the ERK cascade have been elucidated, the mechanisms by which the components of the MAP kinase cascade come into physical contact have not been investigated. In this context it is interesting to note that there are multiple upstream regulators of ERK in the hippocampus: NE, DA, nicotinic ACh, muscarinic ACh, histamine, estrogen, serotonin, brain derived neurotrophic factor (BDNF), NMDA receptors, metabotropic glutamate receptors, AMPA receptors, voltage-gated calcium channels, reactive oxygen species, various PKC isoforms, PKA, nitric oxide (NO), NF1, and multiple ras isoforms and homologs. Current Opinion in Neurobiology 2004, 14:311–317
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Mitogen-activated protein kinases in synaptic plasticity and memory Sweatt 313
Figure 2
neurofibromatosis, specifically disruption of ras/ERK signaling in the hippocampus [20]. CA1 neuron
Back-propagating action potential 1 PKA 2
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ERK ↓ Kv
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Current Opinion in Neurobiology
A model for ERK regulation of dendritic potassium channels. An emerging hypothesis is that complex b-adrenergic receptor regulation of Kv4.2 contributes to increasing the sophistication of information processing that can be achieved by the hippocampal pyramidal neuron. Specifically, it can allow for 3-way coincidence detection — consider the following example, which is hypothetical at this point but based on a number of recent studies [32,33,34, 35–37]. This example is a combination of the NMDA receptor in its classical role as a detector of coincident membrane depolarization and synaptic glutamate, plus b-adrenergic receptor activation of ERK, and potassium channel regulation by ERK. Imagine that LTP will be triggered by a back-propagating action potential (b-AP), caused in response to a strong action-potential-triggering input at a distal synapse, coupled with local synaptic glutamate. LTP results because the NMDA receptor senses b-AP-associated membrane depolarization coupled with synaptic glutamate at the synapse of interest. In addition, available data indicate that A-type Kþ currents would limit the capacity of the b-AP to reach the synapse and thus depolarize the NMDA receptor, except that a b-adrenergic receptor has activated ERK and down-regulated these channels. Thus, the b-adrenergic receptor has gated the b-AP and allowed it to enter the relevant dendritic region. This allows NMDA receptor activation, and the resulting calcium influx through the NMDA receptor is sufficient to cause robust synaptic LTP. In this example a strong synaptic input at a distal synapse, plus a weak synaptic input, plus one neuromodulatory input (NE), has uniquely triggered lasting synaptic plasticity: 3-way coincidence detection. The model draws directly from data published by Winder and his collaborators [37], O’Dell’s group [36], and us and several of our colleagues [32,33,34,35,50].
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The product of the NF1 gene is neurofibromin, a multidomain molecule that has the capacity to regulate several intracellular processes, including the ERK cascade by serving as a GTPase-activating protein (GAP) for ras. Work from the Silva laboratory demonstrated that some neurofibromatosis-associated NF1 mutations, that is those linked to the mental retardation phenotype, disrupt neurofibromin GAP activity and lead to hyperactivation of ras in the hippocampus. In a sophisticated multidisciplinary series of studies Silva and his co-workers provided compelling evidence that this ras/ERK hyperactivation contributes to hippocampus-dependent learning and memory deficits and disruption of LTP at Schaffer collateral synapses, using their mouse model of neurofibromatosis mental retardation [20]. It is important to note that the basis of these deficits does not appear to be caused by anatomical mis-wiring of the CNS or hippocampus, or to alterations in baseline synaptic connectivity. Rather, the synaptic plasticity and learning deficits are due to dysregulation of signal transduction mechanisms operating in association with acute activitydependent processes of synaptic plasticity. This is just one specific example of an emerging paradigm shift in thinking about human mental retardation. Mental retardation can no longer be thought of as exclusively a developmental problem caused by anatomical derangement, but rather we must now also consider that disruption of ongoing plasticity-related synaptic signal transduction mechanisms will play a part as well [20,21–23]. These recent studies into neurofibromatosis-associated mental retardation have given new insights into the molecular underpinnings of human cognitive processing, in particular to mechanisms likely to contribute to learning and memory. Importantly in the present context, they specifically implicate the hippocampal ras/ERK pathway in human mental retardation and by extension in normal learning and memory as well. What is it that ERK is doing in order to help make synapses plastic and the brain mnemonic? For the remainder of this brief review I focus on a number of interesting new potential roles for ERK in this context. These are in addition to its canonical role as a regulator of gene expression [24–30], which I do not cover here.
Extracellular-signal regulated kinase regulation of potassium channels — dendritic information processing The N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor is the prototype ‘cognitive molecule’ — this receptor has immediate appeal in the context of molecular information processing because it can serve Current Opinion in Neurobiology 2004, 14:311–317
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as a coincidence detector. Thus, the NMDA receptor is selectively opened upon two simultaneous actions: binding of glutamate and depolarization of the membrane in which it resides. One theme that is beginning to emerge from work on dendritic potassium channels in hippocampal pyramidal neurons is that Kþ channels might provide the neuron with additional information processing capacity — they do this through controlling the membrane depolarization that the NMDA receptor senses. Specifically, the emerging model is that voltage-dependent Kþ channels of the Kv4.x family regulate membrane depolarization at the dendritic spine level through controlling local membrane depolarization or through regulating the arrival and/or effects of dendritic back-propagating action potentials (see Birnbaum et al. [31] for a review). Thus, Kþ channels appear to operate as partners of the NMDA receptor, in that they allow a more sophisticated level of information processing by controlling the membrane potential that the NMDA receptor detects. This is especially important because Kþ channels, in particular A-type channels, such as those encoded by Kv4 family members, are themselves subject to modulation. The Kþ channels detect and integrate biochemical signals and provide this mechanism for conferring more sophisticated control over NMDA receptor activation. Important recent work has shown that the modulation of dendritic Kþ channel function by the protein kinase A (PKA) and PKC cascades, or by b-adrenergic receptor activators, is dependent on the activation of ERK [32,33,34,35–37]. The molecular mechanism for this modulation appears to be direct phosphorylation of the pore-forming alpha subunit of Kv4-family potassium channels [32,34,35]. This phosphorylation event is hypothesized to cause an alteration in channel properties such that the voltage-dependence of activation is shifted in a depolarizing direction. In other words, greater depolarization is required to open the potassium channels, increasing membrane excitability. This increase in membrane excitability allows for augmented NMDA receptor activation when the membrane is depolarized by the opening of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, or through a back-propagating action potential (see Figure 2). This mechanism is likely to be particularly important in ‘theta-type’ LTP, that is, 5 Hz-stimulation induced LTP [33,36,37]. Theta frequency stimulation mimics an endogenous CA1 neuron firing pattern that rodents manifest when they are learning about their environment. Theta-frequency stimulation causes action potential bursting in area CA1 cells, which can back-propagate into the dendrites and depolarize synapses. Several groups, including the laboratories of Kandel, Winder, and O’Dell [33,36,37] have shown that blocking ERK activation in mouse area CA1 blocks not only the complex Current Opinion in Neurobiology 2004, 14:311–317
spike bursting seen with the theta-frequency stimulation protocol but also the LTP that is so induced. In addition, Winder and co-workers [37] have found that b-adrenergic receptor-mediated modulation of LTP induced with theta-frequency stimulation is blocked by inhibitors of ERK activation. Again, these findings are consistent with a model in which ERK regulation of membrane electrical properties, through control of Kv4-family channels, regulates back-propagating action potentials and controls NMDA receptor activation. What is the role of this complex b-adrenergic receptor regulation of potassium channels and the NMDA receptor? It may contribute to increasing the sophistication of information processing that can be achieved by the hippocampal pyramidal neuron. Specifically, it can allow for 3-way coincidence detection (Figure 2). Under the conditions described above, synaptic potentiation will be selectively triggered only upon the simultaneous presence of: first, synaptic glutamate, second, a back-propagating action potential, and third, norepinephrine (NE) to inhibit Kþ channels and allow the NMDA receptor to sense the depolarization. Moreover, in hippocampal pyramidal neurons various NE, dopamine (DA), serotonin (5HT), and acetylcholine (ACh) receptor subtypes can also couple to activation of ERK in the hippocampus (see Figure 1). Overall then, this mechanism for 3-way coincidence detection might be utilized as a general and powerful means of enhancing dendritic information processing capacity.
Hot areas in the future? To keep the review brief in the last section I tersely highlight three areas that I think are likely areas of rapid and important advancement in the near future. For each area I present a few recent references to give the flavor of new developments.
Ras/extracellular-signal regulated kinase regulation of dendritic spines ERK has recently been implicated as an important regulator of activity-dependent structural changes in hippocampal neurons [38,39]. Specifically, formation and stabilization of dendritic spines involves ERK activation, a role likely to be involved in long-term information storage in the CNS. In an interesting twist, Wu [38] has found that these effects of ERK require repeated spaced stimulation, indicating that ERK is somehow involved in signal integration over fairly long time periods.
Extracellular-signal regulated kinase regulation of local dendritic protein synthesis It is becoming clear that ERK will be a crucial regulator of protein synthesis in dendrites. This reprises one of the general roles of ERK in non-neuronal cells, in which MAPKs in general are pluripotent regulators of processes www.sciencedirect.com
Mitogen-activated protein kinases in synaptic plasticity and memory Sweatt 315
involved in mitogenic stimulation, that is, preparing the cell for replication. In non-dividing adult neurons, however, the system must have been adapted to more subtle modes of regulation and specificity of targeting, because regulation of protein synthesis has been adapted specifically to activity-dependent processes leading to subtle long-term structural changes (see [40,41], for example). Landau and co-workers [42] have already identified calcium/calmodulin dependent kinase II (CaMKII) as one specific target of ERK-dependent changes in protein synthesis in hippocampal neurons, an effect specifically investigated in the context of LTP-inducing stimulation. In a recent technical tour-de-force, Kelleher, Govindarajan and co-workers [43] have used transgenic approaches and a multidisciplinary investigation to implicate ERK directly as a regulator of protein translation required for LTP and memory formation in vivo.
The interplay of extracellular-signal regulated kinase and synaptic structural proteins One of the important areas of recent advancement in the signal transduction field has been the appreciation of the important part that scaffolding proteins play in coordinating and segregating the actions of specific signaling cascades. This important principle in the area of signal transduction has been paralleled in the neurosciences by the emerging significance of scaffolding proteins in regulating synaptic function. In the context of this review, scaffolding proteins are likely to be particularly important in regulating MAPK cascades at the synapse. For example, MAPKs are regulated by a wide variety of upstream triggers, including different types of receptors, other signaling cascades, and a variety of ras G protein isoforms (see Figure 1). Currently around twenty different neurotransmitter systems or cellular signaling systems are known to regulate ERK in hippocampal neurons. This raises the important question of how the various upstream regulators maintain specificity in their coupling to MAPKs such as ERK. One contemporary hypothesis in this area is that scaffolding proteins compartmentalize specific pools of MAPKs to maintain fidelity of signaling from specific upstream regulators [44,45,46]. The mirror image of this process might also occur, because there are interesting recent findings suggesting that ERK in turn regulates the expression and localization of scaffolding proteins at synapses as well [47,48,49]. One seminal finding in this area of late is the discovery that ras/ERK regulates AMPA receptor trafficking and expression [49]. Overall this appears to be an area that will yield many new insights into the roles and regulation of ERK in neurons.
Conclusions The studies highlighted in this review describe an emerging understanding of the roles of the ERK/MAPK cascade in learning and memory. Studies using several behavioral www.sciencedirect.com
memory paradigms have implicated ERK as an essential component of the signal transduction mechanisms subserving behavioral memory formation. Many studies have implicated ERK as a crucial player in synaptic and neuronal plasticity — a cellular role that is likely to underlie ERK’s behavioral role in the animal. Molecular studies have indicated the complexities of biochemical regulation of ERK in neurons and have highlighted the variety of likely cellular targets of ERK. Understanding these complexities and varieties of targets will be important for understanding the molecular basis of ERK-mediated behavioral change. I speculate that the complexities and idiosyncrasies of ERK regulation might allow for sophisticated information processing at the biochemical level in neurons — attributes that might make the ERK cascade particularly well-suited for triggering complex and long-lasting behavioral change.
Acknowledgements The work in the author’s laboratory is supported by funding from the National Institutes of Health.
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couples PKA and PKC to cAMP response element binding protein phosphorylation in area CA1 of hippocampus. J Neurosci 1999, 19:4337-4348. 26. Martin KC, Michael D, Rose JC, Barad M, Casadio A, Zhu H, Kandel ER: MAP kinase translocates into the nucleus of the presynaptic cell and is required for long-term facilitation in Aplysia. Neuron 1997, 18:899-912. 27. Impey S, Smith DM, Obrietan K, Donahue R, Wade C, Storm DR: Stimulation of cAMP response element (CRE)-mediated transcription during contextual learning. Nat Neurosci 1998, 1:595-601. 28. Patterson SL, Pittenger C, Morozov A, Martin KC, Scanlin H, Drake C, Kandel ER: Some forms of cAMP-mediated longlasting potentiation are associated with release of BDNF and nuclear translocation of phospho-MAP kinase. Neuron 2001, 32:123-140. 29. Waltereit R, Dammermann B, Wulff P, Scafidi J, Staubli U, Kauselmann G, Bundman M, Kuhl D: Arg3.1/Arc mRNA induction by Ca2R and cAMP requires protein kinase A and mitogenactivated protein kinase/extracellular regulated kinase activation. J Neurosci 2001, 21:5484-5493. 30. Davis S, Vanhoutte P, Pages C, Caboche J, Laroche S: The MAPK/ ERK cascade targets both Elk-1 and cAMP response elementbinding protein to control long-term potentiation-dependent gene expression in the dentate gyrus in vivo. J Neurosci 2000, 20:4563-4572. 31. Birnbaum SG, Varga AW, Yuan L-L, Anderson AE, Sweatt JD, Schrader LA: Structure and function of Kv4-family transient potassium channels. Physiol Rev 2004, In press. 32. Yuan LL, Adams JP, Swank M, Sweatt JD, Johnston D: Protein kinase modulation of dendritic KR channels in hippocampus involves a mitogen-activated protein kinase pathway. J Neurosci 2002, 22:4860-4868. The authors investigated ERK modulation of dendritic A-type Kþ channels in dendrites of CA1 pyramidal neurons. These studies showed that activation of PKA and PKC led to an increase in the amplitude of back-propagating action potentials in distal dendrites through downregulation of transient Kþ channels. Both of these signaling pathways acted through ERK in mediating this reduction in dendritic Kþ current, and biochemical assays using phosphospecific antibodies against ERKphosphorylated Kv4.2 suggested that the modulation of these Kþ channels could be accounted for by the direct phosphorylation of Kv4.2 subunits by ERK. 33. Watanabe S, Hoffman DA, Migliore M, Johnston D: Dendritic KR channels contribute to spike-timing dependent long-term potentiation in hippocampal pyramidal neurons. Proc Natl Acad Sci USA 2002, 99:8366-8371. The authors obtained results from direct patch-clamp recording of hippocampal pyramidal neuron dendrites indicating that ERK activation shifts the voltage-dependent activation of dendritic potassium channels to more depolarized potentials. In other words, dendritic ERK activation appears to suppress potassium channel function and increase membrane excitability. These results support the hypothesis that suppression of dendritic Kþ channels and the resultant boosting of back-propagating action potentials contribute to the induction of NMDA-receptor-dependent LTP in CA1 neurons. 34. Morozov A, Muzzio IA, Bourtchouladze R, Van-Strien N, Lapidus K, Yin D, Winder DG, Adams JP, Sweatt JD, Kandel ER: Rap1 couples cAMP signaling to a distinct pool of p42/44MAPK regulating excitability, synaptic plasticity, learning, and memory. Neuron 2003, 39:309-325. The studies by Yuan et al., Watanabe et al. and Morozov et al. [32–34] demonstrate an important role for ERK in regulating dendritic potassium channels, a role that is likely to contribute to dendritic information processing and the regulation of NMDA receptor activation. The studies by Morozov et al. also implicate these processes in hippocampal LTP and in memory formation in the behaving animal. 35. Adams JP, Anderson AE, Varga AW, Dineley KT, Cook RG, Pfaffinger PJ, Sweatt JD: The A-type potassium channel Kv4.2 is a substrate for the mitogen-activated protein kinase ERK. J Neurochem 2000, 75:2277-2287. 36. Watabe AM, Zaki PA, O’Dell TJ: Coactivation of beta-adrenergic and cholinergic receptors enhances the induction of long-term potentiation and synergistically activates mitogen-activated www.sciencedirect.com
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protein kinase in the hippocampal CA1 region. J Neurosci 2000, 20:5924-5931. 37. Winder DG, Martin KC, Muzzio IA, Rohrer D, Chruscinski A, Kobilka B, Kandel ER: ERK plays a regulatory role in induction of LTP by theta frequency stimulation and its modulation by beta-adrenergic receptors. Neuron 1999, 24:715-726. 38. Wu GY, Deisseroth K, Tsien RW: Spaced stimuli stabilize MAPK pathway activation and its effects on dendritic morphology. Nat Neurosci 2001, 4:151-158. 39. Goldin M, Segal M: Protein kinase C and ERK involvement in dendritic spine plasticity in cultured rodent hippocampal neurons. Eur J Neurosci 2003, 17:2529-2539. The studies by Wu et al. and Goldin and Segal [38,39] highlight a necessity for ERK in stabilizing morphological changes in dendritic spines, a mechanism likely to be relevant to triggering long-lasting changes in neuronal circuit structure. In addition, ERK also can serve as a signal integrator, detecting repeated stimuli delivered over time. 40. Ying SW, Futter M, Rosenblum K, Webber MJ, Hunt SP, Bliss TV, Bramham CR: Brain-derived neurotrophic factor induces longterm potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of Arc synthesis. J Neurosci 2002, 22:1532-1540. 41. Ehlers MD: Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. Nat Neurosci 2003, 6:231-242. 42. Giovannini MG, Blitzer RD, Wong T, Asoma K, Tsokas P, Morrison JH, Iyengar R, Landau EM: Mitogen-activated protein kinase regulates early phosphorylation and delayed expression of Ca2R/calmodulin-dependent protein kinase II in long-term potentiation. J Neurosci 2001, 21:7053-7062. 43. Kelleher RJ, Govindarajan A, Jung HY, Kang H, Tonegawa S: Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell 2004, 116:467-479. The studies by Giovannini et al. and Kelleher et al. [42,43] investigate an emerging new role for ERK in the hippocampus, the regulation of local dendritic protein synthesis. Moreover, these papers directly implicate a necessity for this function of ERK in LTP and memory formation in the behaving animal.
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44. Vanhoose AM, Emery M, Jimenez L, Winder DG: ERK activation by G-protein-coupled receptors in mouse brain is receptor identity-specific. J Biol Chem 2002, 277:9049-9053. 45. Krapivinsky G, Krapivinsky L, Manasian Y, Ivanov A, Tyzio R, Pellegrino C, Ben-Ari Y, Clapham DE, Medina I: The NMDA receptor is coupled to the ERK pathway by a direct interaction between NR2B and RasGRF1. Neuron 2003, 40:775-784. Krapivinsky et al. highlight a new mechanism relevant to ras/ERK signaling, that is scaffolding and structural proteins important in regulating ERK activation. These studies specifically implicate these processes in NMDA receptor coupling to ERK in the hippocampus. 46. Komiyama NH, Watabe AM, Carlisle HJ, Porter K, Charlesworth P, Monti J, Strathdee DJ, O’Carroll CM, Martin SJ, Morris RG et al.: SynGAP regulates ERK/MAPK signaling, synaptic plasticity, and learning in the complex with postsynaptic density 95 and NMDA receptor. J Neurosci 2002, 22:9721-9732. The authors report that the postsynaptic scaffolding protein PSD-95 is one regulator of postsynaptic ras activation, probably involving its interaction with the GTPase activating protein synGAP. Their data also highlight the likelihood of complexity in the interactions of scaffolding and structural proteins with the ras and ERK pathways in neurons. 47. Rosenblum K, Futter M, Voss K, Erent M, Skehel PA, French P, Obosi L, Jones MW, Bliss TV: The role of extracellular regulated kinases I/II in late-phase long-term potentiation. J Neurosci 2002, 22:5432-5441. 48. Kato A, Fukazawa Y, Ozawa F, Inokuchi K, Sugiyama H: Activation of ERK cascade promotes accumulation of Vesl-1S/Homer-1a immunoreactivity at synapses. Brain Res Mol Brain Res 2003, 118:33-44. 49. Zhu JJ, Qin Y, Zhao M, Van Aelst L, Malinow R: Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 2002, 110:443-455. The authors report an important new role for the ras/ERK cascade in the hippocampus — regulating the trafficking and insertion of AMPA receptors. These studies thereby identify an important new target of ras/ERK at central synapses. 50. Hoffman DA, Magee JC, Colbert CM, Johnston D: KR channel regulation of signal propagation in dendrites of hippocampal pyramidal neurons. Nature 1997, 387:869-875.
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