Mitogen-Activated Protein Kinase Upregulates the Dendritic Translation Machinery in Long-Term Potentiation by Controlling the Mammalian Target of Rapamycin Pathway

Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York 10029, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 06/2007; 27(22):5885-94. DOI: 10.1523/JNEUROSCI.4548-06.2007
Source: PubMed


Protein synthesis is required for persistent forms of synaptic plasticity, including long-term potentiation (LTP). A key regulator of LTP-related protein synthesis is mammalian target of rapamycin (mTOR), which is thought to modulate translational capacity by facilitating the synthesis of particular components of the protein synthesis machinery. Recently, extracellularly regulated kinase (ERK) also was shown to mediate plasticity-related translation, an effect that may involve regulation of the mTOR pathway. We studied the interaction between the mTOR and ERK pathways in hippocampal LTP induced at CA3-CA1 synapses by high-frequency synaptic stimulation (HFS). Within minutes after HFS, the expression of multiple translational proteins, the synthesis of which is under the control of mTOR, increased in area CA1 stratum radiatum. This upregulation was detected in pyramidal cell dendrites and was blocked by inhibitors of the ERK pathway. In addition, ERK mediated the stimulation of mTOR by HFS. The possibility that ERK regulates mTOR by acting at a component further upstream in the phosphatidylinositide 3-kinase (PI3K)-mTOR pathway was tested by probing the phosphorylation of p90-S6 kinase, phosphoinositide-dependent kinase 1 (PDK1), and Akt. ERK inhibitors blocked HFS-induced phosphorylation of all three proteins at sites implicated in the regulation of mTOR. Moreover, a component of basal and HFS-induced ERK activity depended on PI3K, indicating that mTOR-mediated protein synthesis in LTP requires coincident and mutually dependent activity in the PI3K and ERK pathways. The role of ERK in regulating PDK1 and Akt, with their extensive effects on cellular function, has important implications for the coordinated response of the neuron to LTP-inducing stimulation.

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    • "The early decrease in the strong rpS6 immunofluorescence signal in somata after the HFS-induced L-LTP suggested HFS-dependent movement of rpS6 from the soma to other subcellular regions. A previous in vitro study revealed that the translational machinery, including rpS6, increases in dendritic regions receiving HFS (Tsokas et al., 2007), and polyribosomes are selectively increased in spines during LTP in the hippocampal CA1 region. However, it was unclear whether LTP induction in vivo triggers the selective targeting of the translational machinery to activated synaptic sites. "
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    ABSTRACT: Late phase long-term potentiation (L-LTP) in the hippocampus is believed to be the cellular basis of long-term memory. Protein synthesis is required for persistent forms of synaptic plasticity, including L-LTP. Neural activity is thought to enhance local protein synthesis in dendrites, and one of the mechanisms required to induce or maintain the long-lasting synaptic plasticity is protein translation in the dendrites. One regulator of translational processes is ribosomal protein S6 (rpS6), a component of the small 40S ribosomal subunit. Although polyribosomes containing rpS6 are observed in dendritic spines, it remains unclear whether L-LTP induction triggers selective targeting of the translational machinery to activated synapses in vivo. Therefore, we investigated synaptic targeting of the translational machinery by observing rpS6 immunoreactivity during high frequency stimulation (HFS) for L-LTP induction in vivo. Immunoelectron microscopic analysis revealed a selective but transient increase in rpS6 immunoreactivity occurring as early as 15 min after the onset of HFS in dendritic spine heads at synaptic sites receiving HFS. Concurrently, levels of the rpS6 protein rapidly declined in somata of granule cells, as determined using immunofluorescence microscopy. These results suggest that the translational machinery is rapidly targeted to activated spines and that this targeting mechanism may contribute to the establishment of L-LTP.
    Full-text · Article · Oct 2015 · Biology Open
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    • " at different levels of the signalling flow is shown . Indeed , the mitogen - activated protein kinases have also been shown to regulate mTORC1 . ERK was found to phosphorylate and inhibit the function of TSC2 , albeit through different mechanisms and at different phosphorylation sites ( Corradetti & Guan , 2006 ) . For instance , a recent study ( Tsokas et al . , 2007 ) showed an inter - esting interplay between ERK and mTOR pathways at CA3 – CA1 synapses : ERK is required for the high frequency stimulation - induced activation of the mTOR pathway in the hippocampus . Fur - ther studies demonstrate a complex interplay among the choliner - gic system , ERK and mTOR . For instance , mTOR is known to ph"
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    ABSTRACT: The purpose of this review is to summarize the present knowledge on the interplay among the cholinergic system, Extracellular signal-Regulated Kinase (ERK) and Mammalian Target of Rapamycin (mTOR) pathways in the development of short and long term memories during the acquisition and recall of the step-down inhibitory avoidance in the hippocampus. The step-down inhibitory avoidance is a form of associative learning that is acquired in a relatively simple one-trial test through several sensorial inputs. Inhibitory avoidance depends on the integrated activity of hippocampal CA1 and other brain areas. Recall can be performed at different times after acquisition, thus allowing for the study of both short and long term memory. Among the many neurotransmitter systems involved, the cholinergic neurons that originate in the basal forebrain and project to the hippocampus are of crucial importance in inhibitory avoidance processes. Acetylcholine released from cholinergic fibers during acquisition and/or recall of behavioural tasks activates muscarinic and nicotinic acetylcholine receptors and brings about a long-lasting potentiation of the postsynaptic membrane followed by downstream activation of intracellular pathway (ERK, among others) that create conditions favourable for neuronal plasticity. ERK appears to be salient not only in long term memory, but also in the molecular mechanisms underlying short term memory formation in the hippocampus. Since ERK can function as a biochemical coincidence detector in response to extracellular signals in neurons, the activation of ERK-dependent downstream effectors is determined, in part, by the duration of ERK phosphorylation itself. Long term memories require protein synthesis, that in the synapto-dendritic compartment represents a direct mechanism that can produce rapid changes in protein content in response to synaptic activity. mTOR in the brain regulates protein translation in response to neuronal activity, thereby modulating synaptic plasticity and long term memory formation. Some studies demonstrate a complex interplay among the cholinergic system, ERK and mTOR. It has been shown that co-activation of muscarinic acetylcholine receptors and β-adrenergic receptors facilitates the conversion of short term to long term synaptic plasticity through an ERK- and mTOR-dependent mechanism which requires translation initiation. It seems therefore that the complex interplay among the cholinergic system, ERK and mTOR is crucial in the development of new inhibitory avoidance memories in the hippocampus.
    Full-text · Article · Jan 2015 · Neurobiology of Learning and Memory
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    • "AKT exhibits synapsemodulating properties, in particular an ability to effect postsynaptic receptor recruitment (Wang et al., 2003). Like resveratrol in the present study, high frequency stimulation can induce AKT Thr308 phosphorylation, without affecting total protein levels (Tsokas et al., 2007; though see Sui et al., 2008). AKT function has been associated with prefrontal cortex structural alterations in both humans and mice (Lai et al., 2006; Tan et al., 2008), together with alterations in social information processing (Lin et al., 2012) and mental health conditions associated with disordered mood, such as depression, autism, bipolar disorder and schizophrenia (De Lacy and King, 2013; Ebert and Greenberg, 2013; Emamian, 2012; Kitagishi et al., 2012; Marsden, 2013; Zheng et al., 2012). "
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    Full-text · Article · Jun 2014 · Journal of Psychiatric Research
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