The MAPK cascade is required for mammalian associative learning
Nature NeurosciencePublished 1 November 1998
Coleen M. Atkins, Joel C. Selcher, Joseph J. Petraitis, James M. Trzăskos, J. David Sweatt
Citations1,086
SJR quartileQ1
SJR score11.20
SNIP4.70
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TL;DR
MAPK activation increased in the rat hippocampus after an associative learning task, contextual fear conditioning, and two other protein kinases known to be activated during hippocampal LTP, protein kinase C and α-calcium/calmodulinprotein kinase II, also were activated in the hippocampus after learning.
Abstract
Mitogen-activated protein kinase (MAPK) is an integral component of cellular signaling during mitogenesis and differentiation of mitotic cells. Recently MAPK activation in post-mitotic cells has been implicated in hippocampal long-term potentiation (LTP), a potential cellular mechanism of learning and memory. Here we investigate the involvement of MAPK in learning and memory in behaving animals. MAPK activation increased in the rat hippocampus after an associative learning task, contextual fear conditioning. Two other protein kinases known to be activated during hippocampal LTP, protein kinase C and alpha-calcium/calmodulin protein kinase II, also were activated in the hippocampus after learning. Inhibition of the specific upstream activator of MAPK, MAPK kinase (MEK), blocked fear conditioning. Thus, classical conditioning in mammals activates MAPK, which is necessary for consolidation of the resultant learning.
Keywords
Neuroscience
Journal of Biological ChemistryPROTEIN MEASUREMENT WITH THE FOLIN PHENOL REAGENT
318,326 Citations1951OliverH. Lowry, NiraJ. Rosebrough +2 more
Procedures are described for measuring protein in solution or after precipitation with acids or other agents, and for the determination of as little as 0.2 gamma of protein.
The Journal of PhysiologyLong‐lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path
7,290 Citations1973T.V.P. Bliss, Terje Lømo
The after‐effects of repetitive stimulation of the perforant path fibres to the dentate area of the hippocampal formation have been examined with extracellular micro‐electrodes in rabbits anaesthetized with urethane.
Journal of Neurology Neurosurgery & PsychiatryLOSS OF RECENT MEMORY AFTER BILATERAL HIPPOCAMPAL LESIONS
7,274 Citations1957William Beecher Scoville, Brenda Milner
It is concluded that the anterior hippocampus and hippocampal gyrus, either separately or together, are critically concerned in the retention of current experience.
The FASEB JournalThe MAPK signaling cascade
3,386 Citations1995Rony Seger, Edwin G. Krebs
This review highlights primarily the first MAPK cascade to be discovered that uses the MEK and ERK isoforms and describes their involvement in different cellular processes, and it is now known that signaling pathways initiated by phorbol esters, iono‐phors, heat shock, and liganda for seven transmembrane receptors use distinct MAPK cascades with little or no cross‐reactivity between them.
Journal of Biological ChemistryIdentification of a Novel Inhibitor of Mitogen-activated Protein Kinase Kinase
3,029 Citations1998Margaret Favata, Kurumi Y. Horiuchi +12 more
The MEK affinity of U0126, its selectivity for MEK over other kinases, and its cellular efficacy suggest that this compound will serve as a powerful tool for in vitro and cellular investigations of mitogen-activated protein kinase-mediated signal transduction.
Behavioral NeuroscienceDifferential contribution of amygdala and hippocampus to cued and contextual fear conditioning.
2,923 Citations1992Russell G. Phillips, Joseph E. LeDoux
An associative roles for the amygdala and a sensory relay role for the hippocampus are suggested in fear conditioning, which is involved in the conditioning of fear responses to simple, modality-specific conditioned stimuli as well as to complex, polymodal stimuli.
ScienceModality-Specific Retrograde Amnesia of Fear
2,486 Citations1992Jeansok J. Kim, Michael S. Fanselow
The results indicate that fear memory is not a single process and that the hippocampus may have a time-limited role in associative fear memories evoked by polymodal (contextual) but not unimodal (tone) sensory stimuli.
CellcPLA2 is phosphorylated and activated by MAP kinase
1,869 Citations1993Lih‐Ling Lin, Markus Wartmann +4 more
Treatment of cells with agents that stimulate the release of arachidonic acid causes increased serine phosphorylation and activation of cytosolic phospholipase A2 (cPLA2).
ScienceDeficient Hippocampal Long-Term Potentiation in α-Calcium-Calmodulin Kinase II Mutant Mice
1,482 Citations1992Alcino J. Silva, Charles F. Stevens +2 more
W Whole cell recordings reveal that postsynaptic mechanisms, including N-methyl-D-aspartate (NMDA) receptor function, are intact and are therefore a suitable model for studying the relation between LTP and learning processes.
ScienceImpaired Spatial Learning in α-Calcium-Calmodulin Kinase II Mutant Mice
1,357 Citations1992Alcino J. Silva, Richard Paylor +2 more
The data considerably strengthen the contention that the synaptic changes exhibited in LTP are the basis for spatial memory.
Experimental NeurologyStudies on single neurons in dorsal hippocampal formation and septum in unrestrained rats
1,340 Citations1973James B. Ranck
Current Opinion in Cell BiologyRegulation of transcription by MAP kinase cascades
1,314 Citations1996Richard Treisman
Kinases belonging to the mitogen-activated protein kinase (MAPK) family are used throughout evolution to control the cellular responses to external signals such as growth factors, nutrient status, stress or inductive signals.
NatureFear conditioning induces associative long-term potentiation in the amygdala
1,312 Citations1997M.T. Rogan, Ursula Stäubli +1 more
It is shown that fear conditioning alters auditory CS-evoked responses in LA in the same way as LTP induction, and these may underlie the long-term associative plasticity that constitutes memory of the conditioning experience.
NeuronCognitive Neuroscience and the Study of Memory
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ScienceCoupling of the RAS-MAPK Pathway to Gene Activation by RSK2, a Growth Factor-Regulated CREB Kinase
1,257 Citations1996Jun Xing, David D. Ginty +1 more
Findings identify a cellular function for RSK2 and define a mechanism whereby growth factor signals mediated by RAS and MAPK are transmitted to the nucleus to activate gene expression.
The Journal of PhysiologyLong‐lasting potentiation of synaptic transmission in the dentate area of the unanaesthetized rabbit following stimulation of the perforant path
1,190 Citations1973T.V.P. Bliss, A. R. Gardner‐Medwin
Potential changes evoked by stimulation of the perforant path have been recorded in the dentate area of the hippocampal formation in chronically prepared unanaesthetized rabbits.
ScienceAutophosphorylation at Thr <sup>286</sup> of the α Calcium-Calmodulin Kinase II in LTP and Learning
1,062 Citations1998Karl-Peter Giese, Nikolai B. Fedorov +2 more
The autophosphorylation of alphaCaMKII at Thr286 appears to be required for LTP and learning.
ScienceRegulatory Phosphorylation of AMPA-Type Glutamate Receptors by CaM-KII During Long-Term Potentiation
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Induction of LTP increased the phosphorus-32 labeling of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA-Rs), which mediate rapid excitatory synaptic transmission and provides a postsynaptic molecular mechanism for synaptic plasticity.
Brain ResearchPatterned stimulation at the theta frequency is optimal for the induction of hippocampal long-term potentiation
1,039 Citations1986John Larson, Darryl Wong +1 more
The results indicate that patterns of stimulation resembling spike discharge patterns of hippocampal neurons in animals in exploratory situations are effective in inducing LTP and suggest temporal constraints on the mechanisms involved in triggering synaptic plasticity.
Journal of Biological ChemistryA Requirement for the Mitogen-activated Protein Kinase Cascade in Hippocampal Long Term Potentiation
858 Citations1997Joey D. English, J. David Sweatt
It is reported that theMAPK cascade is required for hippocampal long term potentiation (LTP), a robust and widely studied form of synaptic plasticity, and the first demonstration of a role for the MAPK cascade in the activity-dependent modification of synaptic connections between neurons in the adult mammalian nervous system is provided.
NatureFear conditioning induces a lasting potentiation of synaptic currents in vitro
779 Citations1997Margaret McKernan, Patricia Shinnick‐Gallagher
One of the first in vitro measures of synaptic plasticity resulting from emotional learning by whole animals is reported, reporting a long-lasting increase in the synaptic efficacy of the MGN–LA pathway attributable to fear-conditioning itself, rather than an electrically induced model of learning.
Behavioral NeuroscienceEffects of amygdala, hippocampus, and periaqueductal gray lesions on short- and long-term contextual fear.
590 Citations1993Jeansok J. Kim, Richard A. Rison +1 more
The results indicate that there are anatomically dissociable short- and long-term conditional fear states.
Journal of Biological ChemistryActivation of p42 Mitogen-activated Protein Kinase in Hippocampal Long Term Potentiation
577 Citations1996Joey D. English, J. David Sweatt
It is demonstrated that p42 MAPK can be regulated in an activity-dependent manner in the hippocampus and identified it as a potential component of the LTP induction cascades in area CA1, suggesting that p 42 MAPK might be an important regulator of synaptic plasticity in post-mitotic neurons.
NeuronMAP Kinase Translocates into the Nucleus of the Presynaptic Cell and Is Required for Long-Term Facilitation in Aplysia
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It is shown that MAPK translocates into the nucleus of the presynaptic but not the postsynaptic cell during 5-HT-induced long-term facilitation, which appears to be specifically recruited and necessary for the long- term form of facilitation.
NatureA role for the Ras signalling pathway in synaptic transmission and long-term memory
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Proceedings of the National Academy of SciencesNeurotrophins stimulate phosphorylation of synapsin I by MAP kinase and regulate synapsin I-actin interactions.
393 Citations1996Jasmina N. Jovanovic, Fabio Benfenati +6 more
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Learning & Memoryα7 Nicotinic Receptor Subunits Are Not Necessary for Hippocampal-Dependent Learning or Sensorimotor Gating: A Behavioral Characterization of <i>Acra7</i>-Deficient Mice
298 Citations1998Richard Paylor, Michelle M. Nguyen +4 more
The results of this study show that the absence of alpha7 nAChRs has little impact on normal, base-line behavioral responses, and future studies will examine the contribution ofalpha7nAChR to the enhancement of learning and sensorimotor gating following nicotine treatments.
Behavioral NeuroscienceN-methyl-D-aspartate receptor antagonist APV blocks acquisition but not expression of fear conditioning.
295 Citations1991Jeansok J. Kim, Joseph P. DeCola +2 more
Effects on fear conditioning are parallel to the in vitro effects of APV on the acquisition but not expression of long-term potentiation (LTP) and suggest that endogenously generated NMDA-dependent LTP participates in the neural plasticity underlying fear conditioning.
Neurobiology of Learning and MemoryCorrelation between the Pharmacology of Long-Term Potentiation and the Pharmacology of Memory
226 Citations1995Iván Izquierdo, Jorge H. Medina
The pharmacology of memory was found to be remarkably similar to that of long-term potentiation (LTP), and memories that depend on the HIP, AMY, and MS are affected by drugs given into the three structures.
NeuronInhibition of calcium/calmodulin-dependent protein kinase in drosophila disrupts behavioral plasticity
212 Citations1993Leslie C. Griffith, Lynne Verselis +4 more
A specific peptide inhibitor of CaM kinase is designed and made transgenic Drosophila that express it under control of an inducible promoter, suggesting that CaM Kinase activity is required for plastic behaviors in an intact animal.
The Journal of Cell BiologyPhosphorylation determines the binding of microtubule-associated protein 2 (MAP2) to microtubules in living cells.
201 Citations1991Bernard Brugg, Andrew Matus
The results suggest that the site of phosphate incorporation rather than the amount is the critical factor in determining microtubule binding activity ofMAP2, and the interaction of MAP2 with cellular microtubules may be influenced by additional factors that are not evident in vitro.
NeuronA Million Dollar Question: Does LTP = Memory?
181 Citations1998Charles F. Stevens
The hypothesis is that the normally weak dozen years, to see if they think LTP and LTD form auditory synapses in the amygdala become strengtha basis for memory, and have used a two-alternative, ened by LTP during the training that attaches “fear” to forced-choice design like the question above.
Proceedings of the National Academy of SciencesCa2+/calmodulin-dependent protein kinase II: identification of threonine-286 as the autophosphorylation site in the alpha subunit associated with the generation of Ca2+-independent activity.
179 Citations1988Gerhard Thiel, Andrew J. Czernik +3 more
The sequences obtained for two phosphopeptides derived from secondary chymotryptic digestion of CB-1 confirmed that Thr-286 was the phosphorylated residue.
Journal of Biological ChemistryTransient Activation of Cyclic AMP-dependent Protein Kinase during Hippocampal Long-term Potentiation
160 Citations1996Erik D. Roberson, J. David Sweatt
Results indicate that at the initiation of LTP, NMDA receptor stimulation leads to transient activation of PKA, and support a role for PKA in the induction of L TP, and developed an in vitro assay which is useful for selective and accurate measurement of stimulus-induced changes in PKA activity in hippocampal slices.
Neurosciencep42 mitogen-activated protein kinase in brain: Prominent localization in neuronal cell bodies and dendrites
158 Citations1993Rachel S. Fiore, Virginia E. Bayer +4 more
Immunohistochemical studies presented in this paper demonstrate prominent staining for p42 mitogen-activated protein kinase in neuronal cell bodies and dendrites, suggesting this kinase is likely to play a key role in postsynaptic signal transduction.
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Journal of NeuroscienceInduction of a Specific Olfactory Memory Leads to a Long-Lasting Activation of Protein Kinase C in the Antennal Lobe of the Honeybee
128 Citations1998Lore Grünbaum, Uli Müller
The constitutive PKC in the antennal lobe seems to contribute to the early phase of memory that is induced by multiple-trial conditioning, which is related to multiple conditioning trials inducing a memory different from that induced by a single conditioning trial.
Learning & MemoryA biochemist's view of long-term potentiation.
118 Citations1996Erik D. Roberson, Joey D. English +1 more
This review surveys the molecular mechanisms of long-term potentiation (LTP) from the point of view of a biochemist, focusing on evidence for the involvement of various second messengers and their effectors as well as the biochemical strategies employed in each phase to convert a transient signal into a lasting change in the neuron.
Behavioural Brain ResearchHyperactivity, hyper-reactivity, and sensorimotor deficits induced by low doses of the N-methyl-d-aspartate non-competitive channel blocker MK801
105 Citations1992Eric L. Hargreaves, Donald P. Cain
The behavioral effects of MK801 were characterized as a syndrome of hyperactivity, hyper-reactivity, and sensorimotor deficits, which has been claimed to induce deficits similar to hippocampal lesions.
PubMedMammalian MAP kinase modules: how to transduce specific signals.
104 Citations1997Anne Brunet, Jacques Pouysségur
MAPK modules are composed of a cascade of three intracellular protein kinases which are activated successively by phosphorylation events and, by the ability of MAPK to translocate into the nucleus and phosphorylate nuclear targets such as transcription factors, they relay extracellular signals into a genomic response.
Journal of NeurosciencePhosphorylation of Mitogen-Activated Protein Kinase by One-Trial and Multi-Trial Classical Conditioning
87 Citations1998Terry Crow, Juan‐Juan Xue‐Bian +3 more
Results show that the ERK–MAPK signaling pathway is activated in Pavlovian conditioning of Hermissenda, and after conditioning and behavioral testing, the conditioned animals showed significantly greater phosphorylation of ERK compared with the pseudo-random controls.
Behavioral and Neural BiologyIntrahippocampal or intraamygdala infusion of KN62, a specific inhibitor of calcium/calmodulin-dependent protein kinase II, causes retrograde amnesia in the rat
81 Citations1994Claudia Wolfman, Cyntia Fin +6 more
The data suggest that the early phase of memory requires intact CaM-II activity in the amygdala and hippocampus and support the hypothesis that memory involves long-term potentiation initiated at the time of training in both structures.
Behavioral and Neural BiologyPost-training intrahippocampal infusion of protein kinase C inhibitors causes amnesia in rats
71 Citations1994Diana Jerusalinsky, Jorge Alberto Quillfeldt +4 more
The results support the suggestion that memory involves long-term potentiation initiated at the time of training in the hippocampus, and block the development of long- term potentiation when administered in the first 2 h after induction.
NeuroreportRat gustatory memory requires protein kinase C activity in the amygdala and cortical gustatory area
59 Citations1997Yasunobu Yasoshima, Takashi Yamamoto
The results show that PKC activity in the GC and AMY has a key role in the acquisition phase of CTA, but not in the retrieval phase, and suggest that the GC is concerned with information processing of the CS, and that the AMY is involved in the CS–US association.
Brain ResearchSpatial learning alters hippocampal calcium/calmodulin-dependent protein kinase II activity in rats
58 Citations1996Soon-Eng Tan, Keng‐Chen Liang
The activation of CaM-kinase II in the hippocampus is not only correlated to the degree of spatial training on the Morris water maze, but may also underlie the neural mechanism subserving spatial memory.
Journal of NeurochemistryProtected‐Site Phosphorylation of Protein Kinase C in Hippocampal Long‐Term Potentiation
58 Citations1998J. David Sweatt, Coleen M. Atkins +6 more
A “protected site” model of PKC autophosphorylation is proposed, whereby the conformation ofPKC regulates accessibility of the phosphates to phosphatase, which might be a general biochemical mechanism for the generation of stable, long‐lasting physiologic changes.
NeuropharmacologyEffects of the metabotropic glutamate receptor antagonist MCPG on spatial and context-specific learning
52 Citations1996Fabio Bordi, Clara Marcon +2 more
The experiments indicate that MCPG-sensitive metabotropic receptors may be required for only a restricted subset of spatial learning tasks, while NMDA receptors may play an integral role in all spatial learning.
Behavioural Brain ResearchInvestigations on the role of hippocampal protein kinase C on memory processes: pharmacological approach
30 Citations1996Xavier Nogués, Robert Jaffard +1 more
Investigations on the functional involvement of hippocampal protein kinase C in learning and long-term retention of spatial discrimination in a radial maze point to an involvement of hippocampus in the acquisition of information destined for long- term storage.
Brain ResearchInhibitory avoidance learning alters the amygdala calcium/calmodulin-dependent protein kinase II activity in rats
28 Citations1997Soon‐Eng Tan, Keng‐Chen Liang
Results indicated that the activation of amygdala CaM-kinase II in the amygdala is associated with the affective learning behavior, and may be one of the neural mechanisms underlying formation of affective memory.