Mechanisms of cAMP-induced sustained activation of extracellular signal-regulated kinase in the hippocampus (original) (raw)
2003
The extracellular signal-regulated kinase (ERK) cascade can transduce cell-surface signals to the nucleus in post-synaptic neurons during hippocampus-dependent learning and hippocampusdependent synaptic plasticity, yet, whether the cascade can convey information about stimulus frequency or synaptic modification direction to the nucleus during plasticity events has not been addressed. The objective of the current study was to investigate whether ERK regulation differs as a function of stimulus frequency and in accordance with synaptic modification direction by comparing ERK regulation during LTP in area CA1 of the hippocampus in vivo to previous findings for ERK regulation during LTD in area CA1 in vivo . The ultimate goal was to determine whether ERK functions as a general or as a specific plasticity kinase during synaptic plasticity events in the hippocampus. Using a combination of in vivo electrophysiology, pharmacology and Western blot analysis, I demonstrate that: (1) LTP induced by high-frequency stimulation applied to commissural fiber inputs to area CA1 pyramidal cells in the adult hippocampus in vivo is accompanied by a rapid yet transient increase in ERK2 activation; (2) blockade of NMDA receptors by MK-801 blocks both LTP induction and the associated increase in ERK2 activation; (3) HFS delivered in the presence of the ERK kinase inhibitor SL327 fails to produce a persistent potentiation; (5) phosphorylation of the transcriptional regulator cAMP response element-binding protein (CREB) is increased after HFS; and (6) inhibition of ERK activation by SL327 blocks this observed increase in pCREB.
Phosphorylation plays important roles in several processes including synaptic plasticity and memory. The critical role of extracellular signal-regulated kinase (ERK) in these processes is well established. ERK is activated in a sustained manner by different stimuli. However, the mechanisms of sustained ERK activation are not completely understood. Here we show that KCl depolarization-induced sustained ERK activation in the hippocampal slices is critically dependent on protein synthesis and transcription. In addition, the sustained ERK activation requires receptor tyrosine kinase(s) activity. In support of a role for a growth factor in sustained ERK activation, KCl depolarization enhances the level of brain-derived neurotrophic factor (BDNF). Furthermore, BDNF antibody blocks KCl-induced sustained ERK activation. These results suggest a positive feedback loop in which depolarization-induced BDNF maintains ERK activation in the sustained phase. A ctivity-dependent post-translational protein modifications such as phosphorylation play crucial roles in synaptic plasticity and memory. The extracellular signal-regulated kinase (ERK) plays pivotal roles in these processes in invertebrates as well as vertebrates 1–3. For example, in Aplysia, ERK is activated by a pattern of serotonin application that induces long-term facilitation (LTF) of sensory motor (SN-MN) synapses 4, 5. In addition, ERK activity is required for LTF of SN-MN synapses 6. Furthermore, ERK activity is required for long-lasting forms of memory for sensitization 5. In the vertebrate system, long-term potentiation (LTP) is widely studied as a candidate cellular mechanism of memory 7,8. ERK is activated by LTP-inducing stimuli, and ERK activity is required for LTP 9,10. Furthermore, ERK is activated by memory training and different kinds of memories such as fear conditioning, spatial memory and taste memory are critically dependent upon ERK activity 11–15. The late phases of LTP and memory require translational and transcriptional events. ERK can regulate protein synthesis 16 as well as transcription 17,18. Thus, ERK has diverse functions that contribute to synaptic plasticity and memory formation. Several studies have shown that ERK is activated in a sustained manner by different stimuli. For example, Wu et al. 19 showed that repeated depolarization events with KCl activate ERK that lasts for at least 1 h (sustained activation). Sharma and colleagues 5 found that serotonin induces sustained ERK activation in Aplysia neurons. In addition, sustained ERK activation has been observed with brain-derived neurotrophic factor (BDNF) 19,20. Ahmed and Frey 21 and Schmitt et al. 22 showed that LTP-inducing stimuli cause sustained ERK activation in the hippocampal slices. Swank and Sweatt 23 observed a sustained activation profile of ERK after taste memory training. Recently, Michel et al. 24 found that associative memory training induces sustained ERK activation in the buccal ganglia of Aplysia. Considerable information is available regarding the processes involved in initial ERK activation 3,25. In contrast, little is known about the mechanisms involved in sustained ERK activation. In this study, using KCl depolarization of hippocampal slices, we have investigated the processes that are involved in sustained ERK activation.
Differential Role of Hippocampal cAMP-Dependent Protein Kinase in Short and Long-Term Memory
Neurochemical Research, 2000
One-trial step-down inhibitory (passive) avoidance training is followed by two peaks of cAMP-dependent protein kinase (PKA) activity in rat CA1: one immediately after training and the other 3 h later. The second peak relies on the first: Immediate posttraining infusion into CA1 of the inhibitor of the regulatory subunit of PKA, Rp-cAMPS, at a dose that reduces PKA activity during less than 90 min, cancelled both peaks. Long-term memory (LTM) of this task measured at 24 h depends on the two peaks: Rp-cAMPS given into CA1 0 or 175 min posttraining, but not between those times, blocked LTM. However, the effect of immediate posttraining Rp-cAMPS on LTM could not be reversed by the activator of the regulatory subunit of PKA, Sp-cAMPS, given at 180 min, which suggests that, for LTM, the first peak may be more important than the second. When given at 0, 22, 45, or 90, but not at 175 min from training, Rp-cAMPS blocked short-term memory (STM) measured at 90 or 180 min. This effect of immediate posttraining Rp-cAMPS infusion on STM but not that on LTM was readily reversed by Sp-cAMPS infused 22 min later. On its own, Sp-cAMPS had effects exactly opposite to those of the inhibitor. It enhanced LTM when given at 0 or 175 min from training, and it enhanced STM when given at 0, 22, 45, or 90 min from training. These findings show that STM and LTM formation require separate PKA-dependent processes in CA1. STM relies on the continued activity of the enzyme during the first 90 min. LTM relies on the two peaks of PKA activity that occur immediately and 180 min posttraining.
Journal of Neuroscience, 2007
Pyramidal neurons in the piriform cortex from olfactory-discrimination-trained rats show enhanced intrinsic neuronal excitability that lasts for several days after learning. Such enhanced intrinsic excitability is mediated by long-term reduction in the postburst afterhyperpolarization (AHP), which is generated by repetitive spike firing. AHP reduction is attributable to decreased conductance of a calciumdependent potassium current, the sI AHP . We have previously shown that such learning-induced AHP reduction is maintained by PKC activation. However, the molecular machinery underlying such long-lasting modulation of intrinsic excitability is yet to be fully described. Here we examine whether the extracellular signal-regulated kinase I/II (ERKI/II) pathway, which is known to be crucial in learning, memory, and synaptic plasticity processes, is instrumental for the long-term maintenance of learning-induced AHP reduction. PD98059 or UO126, which selectively block MEK, the upstream kinase of ERK, increased the AHP in neurons from trained rats but not in neurons from naive and pseudo-trained rats. Consequently, the differences in AHP amplitude and neuronal adaptation between neurons from trained rats and controls were abolished. This effect was not mediated by modulation of basic membrane properties. In accordance with its effect on neuronal excitability, the level of activated ERK in the membranal fraction was significantly higher in piriform cortex samples taken from trained rats. In addition, the PKC activator OAG (1-oleoyl-20acety-sn-glycerol), which was shown to reduce the AHP in neurons from control rats, had no effect on these neurons in the presence of PD98059. Our data show that ERK has a key role in maintaining long-lasting learning-induced enhancement of neuronal excitability.
Journal of Neurochemistry, 2008
The late phase of long-term potentiation (LTP) requires activation of the mammalian target of rapamycin (mTOR) pathway and synthesis of new proteins. mTOR regulates protein synthesis via phosphorylation of 4E-binding proteins (4E-BPs) and S6K, and via selective up-regulation of 5′ terminal oligopyrimidine (5′ TOP) mRNAs that encode components of the translational machinery. In this study, we explored the regulation of 5′ TOP mRNAs during late-LTP (L-LTP). Synaptic plasticity was studied at Schaffer collateral-CA1 pyramidal cell synapses in rat organotypic hippocampal slices. Forskolin, an adenylate cyclase activator, induced L-LTP in organotypic slices that was mTOR-dependent. To determine if 5′ TOP mRNAs are specifically up-regulated during L-LTP, we generated a 5′ TOP-myr-dYFP reporter to selectively monitor 5′ TOP translation. Confocal imaging experiments in cultured slices revealed an increase in somatic and dendritic fluorescence after forskolin treatment. This up-regulation was dependent on an intact TOP sequence and was mTOR, extracellular signal-regulated kinase (ERK), and phosphatidylinositol 3-kinase (PI3K)-dependent. Our findings indicate that forskolin induces L-LTP in hippocampal neurons and up-regulates 5′ TOP mRNAs translation via mTOR, suggesting that up-regulation of the translational machinery is a candidate mechanism for the stabilization of LTP.
Abbreviated Title : The effect of chronic disruption of ERK signaling on the hippocampus
2017
affect spatial memory retention and LTP in the same manner as acute blockade of the ERK pathway. Abbreviated Title: The effect of chronic disruption of ERK signaling on the hippocampus. Authors: Joseph Vithayathil 1 , Joanna Pucilowska 1 , David Friel 1 , and Gary E. Landreth 1 1 Department of Neurosciences, Case Western Reserve University, Cleveland Ohio, United States of America, 44106 Corresponding Author: Note address change Gary E. Landreth Stark Neuroscience Research Institute, NB214C Indiana University School of Medicine 315 W 15 th St. Indianapolis, IN 46202 Ph: 317-278-7820 e-mail: glandret@iu.edu Manuscript Details: 34 pages, 5 figures Total Characters (with spaces): 52893
Postsynaptic Mechanisms Are Essential for Forskolin-Induced Potentiation of Synaptic Transmission
Journal of Neurophysiology, 2005
Sokolova, Irina V., Henry A. Lester, and Norman Davidson. Postsynaptic mechanisms are essential for forskolin-induced potentiation of synaptic transmission. . It has been demonstrated that stimulation of protein kinase A (PKA) results in enhanced synaptic transmission in the hippocampus and other brain areas. To investigate mechanisms of the PKA-mediated potentiation of synaptic transmission, we used rat hippocampal embryonic cultures. In low-density cultures, paired recordings under the perforated patch demonstrated that 15-min forskolin treatment produced longlasting potentiation of evoked excitatory postsynaptic currents (eEPSCs) mediated by the cAMP/PKA pathway. eEPSC amplitudes increased to 240 Ϯ 10% of baseline after 15 min of forskolin treatment (early). After forskolin washout, eEPSCs declined to a potentiated level. Potentiation was sustained for Ն85 min after forskolin washout and, 60 min after forskolin washout, constituted 152 Ϯ 7% of baseline (late potentiation). Disruption of presynaptic processes with the whole cell configuration and internal solution containing PKA inhibitor peptide did not affect forskolin-induced potentiation. Disruption of postsynaptic processes, in contrast, impaired early potentiation and abolished late potentiation. Study of mEPSCs confirmed the contribution of postsynaptic mechanisms. Forskolin-induced enhancement of mEPSC frequency observed under the perforated patch was attenuated by the whole cell configuration. Forskolin also induced an increase of mEPSC amplitudes in the perforated patch, but not in the whole cell, experiments. Potentiation of eEPSCs was not activity dependent, persisting in the absence of stimulation. NMDA receptor blockade did not abolish forskolin-induced potentiation. In summary, we demonstrate that forskolin-induced potentiation of eEPSCs was mediated by postsynaptic mechanisms, presumably by upregulation of AMPA receptors by phosphorylation.
Proceedings of The National Academy of Sciences, 1997
cAMP͞cAMP-dependent protein kinase (PKA) signaling pathway has been recently proposed to participate in both the late phase of long term potentiation in the hippocampus and in the late, protein synthesis-dependent phase of memory formation. Here we report that a late memory consolidation phase of an inhibitory avoidance learning is regulated by an hippocampal cAMP signaling pathway that is activated, at least in part, by D 1 ͞D 5 receptors. Bilateral infusion of SKF 38393 (7.5 g͞side), a D 1 ͞D 5 receptor agonist, into the CA 1 region of the dorsal hippocampus, enhanced retention of a step-down inhibitory avoidance when given 3 or 6 h, but not immediately (0 h) or 9 h, after training. In contrast, full retrograde amnesia was obtained when SCH 23390 (0.5 g͞side), a D 1 ͞D 5 receptor antagonist, was infused into the hippocampus 3 or 6 h after training. Intrahippocampal infusion of 8Br-cAMP (1.25 g͞side), or forskolin (0.5 g͞side), an activator of adenylyl cyclase, enhanced memory when given 3 or 6 h after training. KT5720 (0.5 g͞side), a specific inhibitor of PKA, hindered memory consolidation when given immediately or 3 or 6 h posttraining. Rats submitted to the avoidance task showed learning-specific increases in hippocampal 3 H-SCH 23390 binding and in the endogenous levels of cAMP 3 and 6 h after training. In addition, PKA activity and P-CREB (phosphorylated form of cAMP responsive element binding protein) immunoreactivity increased in the hippocampus immediately and 3 and 6 h after training. Together, these findings suggest that the late phase of memory consolidation of an inhibitory avoidance is modulated cAMP͞PKA signaling pathways in the hippocampus.
Protein Kinases and Long-Term Potentiation
Annals of The New York Academy of Sciences, 1991
Excitatory synapses in the hippocampus, and in some other neural tissues, undergo a long-lasting increase in their efficacy when they are heavily used. This potentiating effect is proposed to function as a cellular mechanism for the formation of memory and is very prominent in the hippocampus, a site where the consolidation of experience into long-term memory is thought to occur. When the excitatory synapses are strongly and repetitively activated for brief periods of time, they undergo an increase in strength that has been shown to last several hours or even weeks after induction. This usedependent increase in synaptic efficacy has been termed long-term potentiation (LTP).