Visual Stimulation Activates ERK in Synaptic and Somatic Compartments of Rat Cortical Neurons with Parallel Kinetics

Boggio, Elena; Putignano, Elena; Sassoè‐Pognetto, Marco; Pizzorusso, Tommaso; Giustetto, Maurizio

doi:10.1371/journal.pone.0000604

Cited by 41 publications

(37 citation statements)

References 59 publications

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“…However, growing experimental evidence suggests that this pathway also exerts other fast actions mediated by phosphorylation of synaptic protein substrates (Sweatt, 2004;Boggio et al, 2007). Bioinformatic analysis of Helix, Aplysia, and other gastropod synapsin proteins that display a quite well-conserved primary sequence, revealed the presence of two putative MAPK/Erk phosphorylation sites in the B-domain, consistent with the localization of mammalian synapsin phosphorylation sites 4 and 5.…”

Section: Discussionsupporting

confidence: 53%

“…Moreover, it has been proposed that the MAPK/Erk pathway participates in long-term synaptic plasticity by regulating the activity of transcriptional factors upon nuclear translocation . Some studies show that MAPKs are also present and active in synaptic terminals, suggesting that this pathway might have several functions in distinct subcellular compartments during shortand long-term plasticity, acting through phosphorylation of synaptic targets, including synapsin (Sweatt, 2004;Boggio et al, 2007). Some studies have excluded the involvement of the MAPK/Erk pathway in short-term heterosynaptic plasticity Purcell et al, 2003;Phares and Byrne, 2005).…”

Section: Introductionmentioning

confidence: 99%

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MAPK/Erk-dependent phosphorylation of synapsin mediates formation of functional synapses and short-term homosynaptic plasticity

Giachello

Fiumara

Giacomini³

et al. 2010

Journal of Cell Science

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SummaryMAPK/Erk is a protein kinase activated by neurotrophic factors involved in synapse formation and plasticity, which acts at both the nuclear and cytoplasmic level. Synapsin proteins are synaptic-vesicle-associated proteins that are well known to be MAPK/Erk substrates at phylogenetically conserved sites. However, the physiological role of MAPK/Erk-dependent synapsin phosphorylation in regulating synaptic formation and function is poorly understood. Here, we examined whether synapsin acts as a physiological effector of MAPK/Erk in synaptogenesis and plasticity. To this aim, we developed an in vitro model of soma-to-soma paired Helix B2 neurons, that establish bidirectional excitatory synapses. We found that the formation and activity-dependent short-term plasticity of these synapses is dependent on the MAPK/Erk pathway. To address the role of synapsin in this pathway, we generated non-phosphorylatable and pseudo-phosphorylated Helix synapsin mutants at the MAPK/Erk sites. Overexpression experiments revealed that both mutants interfere with presynaptic differentiation, synapsin clustering, and severely impair post-tetanic potentiation, a form of short-term homosynaptic plasticity. Our findings show that MAPK/Erk-dependent synapsin phosphorylation has a dual role both in the establishment of functional synaptic connections and their short-term plasticity, indicating that some of the multiple extranuclear functions of MAPK/Erk in neurons can be mediated by the same multifunctional presynaptic target.

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Section: Discussionsupporting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

MAPK/Erk-dependent phosphorylation of synapsin mediates formation of functional synapses and short-term homosynaptic plasticity

Giachello

Fiumara

Giacomini³

et al. 2010

Journal of Cell Science

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“…A major functional form of mGluR1 and 5 was seen as dimers in cerebellar and striatal neurons, similar to those observed previously [35, 36]. As to ERK, a sub-pool of ERK resides in neuronal peripheral structures, such as postsynaptic dendritic spines [13, 14, 37]. A major ERK2 band was found at synaptic sites in rat striatal and prefrontal cortical neurons [16].…”

Section: Resultssupporting

confidence: 80%

Synaptic ERK2 Phosphorylates and Regulates Metabotropic Glutamate Receptor 1 In Vitro and in Neurons

et al. 2016

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A synaptic pool of extracellular signal-regulated kinases (ERK) controls synaptic transmission, although little is known about its underlying signaling mechanisms. Here, we found that synaptic ERK2 directly binds to postsynaptic metabotropic glutamate receptor 1a (mGluR1a). This binding is direct and the ERK-binding site is located in the intracellular C-terminus (CT) of mGluR1a. Parallel with this binding, ERK2 phosphorylates mGluR1a at a cluster of serine residues in the distal part of mGluR1a-CT. In rat cerebellar neurons, ERK2 interacts with mGluR1a at synaptic sites, and active ERK constitutively phosphorylates mGluR1a under normal conditions. This basal phosphorylation is critical for maintaining adequate surface expression of mGluR1a. ERK is also essential for controlling mGluR1a signaling in triggering distinct postreceptor signaling transduction pathways. In summary, we have demonstrated that mGluR1a is a sufficient substrate of ERK2. ERK that interacts with and phosphorylates mGluR1a is involved in the regulation of the trafficking and signaling of mGluR1.

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“…Increasing evidences indicate that ERK signaling may be triggered in synaptic structures by direct neuronal activation or behavioral stimuli (6,16,17,(40)(41)(42). However, the physiological mechanisms determining the subcellular targeting of pERK remain unclear.…”

Section: Subcellular Targeting Of Erk Activation During Synaptic Plasmentioning

confidence: 99%

ERK activation in axonal varicosities modulates presynaptic plasticity in the CA3 region of the hippocampus through synapsin I

Vara

Onofri

Benfenati

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Activity-dependent changes in the strength of synaptic connections in the hippocampus are central for cognitive processes such as learning and memory storage. In this study, we reveal an activity-dependent presynaptic mechanism that is related to the modulation of synaptic plasticity. In acute mouse hippocampal slices, high-frequency stimulation (HFS) of the mossy fiber (MF)-CA3 pathway induced a strong and transient activation of extracellular-regulated kinase (ERK) in MF giant presynaptic terminals. Remarkably, pharmacological blockade of ERK disclosed a negative role of this kinase in the regulation of a presynaptic form of plasticity at MF-CA3 contacts. This ERK-mediated inhibition of post-tetanic enhancement (PTE) of MF-CA3 synapses was both frequency-and pathway-specific and was observed only with HFS at 50 Hz. Importantly, blockade of ERK was virtually ineffective on PTE of MF-CA3 synapses in mice lacking synapsin I, 1 of the major presynaptic ERK substrates, and triple knockout mice lacking all synapsin isoforms displayed PTE kinetics resembling that of wildtype mice under ERK inhibition. These findings reveal a form of short-term synaptic plasticity that depends on ERK and is finely tuned by the firing frequency of presynaptic neurons. Our results also demonstrate that presynaptic activation of the ERK signaling pathway plays part in the activity-dependent modulation of synaptic vesicle mobilization and transmitter release.MAP kinase ͉ mossy fibers ͉ post-tetanic potentiation T he extracellular-regulated kinase (ERK) signaling pathway plays a crucial role in the regulation of activity-dependent changes in the strength of synaptic transmission in the hippocampus (1, 2). Indeed, multiple studies have shown that altering the normal function of ERK causes severe impairments of both short-and long-term forms of synaptic plasticity at hippocampal synapses (3-6, but see also ref. 7). Remarkably, behavioral analyses of animals with altered ERK signaling have revealed a crucial involvement of this cascade in learning and memory (8-10), supporting the idea that ERK-dependent synaptic plasticity is essential for cognitive processes.Because potential molecular substrates of ERK are present in distinct neuronal compartments (2), the precise subcellular location in which ERK activation occurs is a major determinant of ERK function. For example, phosphorylated ERK translocates into the nucleus and regulates gene expression in response to synaptic activity by directly or indirectly phosphorylating transcription factors (2,11,12). Moreover, there is increasing evidence that ERK phosphorylates target proteins in both dendritic (13-15) and axonal compartments (16,17). Synapsin I (Syn I), a synaptic vesicleassociated phosphoprotein implicated in the regulation of synaptic strength, is a major ERK substrate in nerve terminals and presents 3 ERK-dependent phosphorylation sites (18,19). Interestingly, it has been shown that ERK phosphorylation regulates the interaction of Syn I with the actin cytoskeleton, a mechanism that is...

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Visual Stimulation Activates ERK in Synaptic and Somatic Compartments of Rat Cortical Neurons with Parallel Kinetics

Cited by 41 publications

References 59 publications

MAPK/Erk-dependent phosphorylation of synapsin mediates formation of functional synapses and short-term homosynaptic plasticity

MAPK/Erk-dependent phosphorylation of synapsin mediates formation of functional synapses and short-term homosynaptic plasticity

Synaptic ERK2 Phosphorylates and Regulates Metabotropic Glutamate Receptor 1 In Vitro and in Neurons

ERK activation in axonal varicosities modulates presynaptic plasticity in the CA3 region of the hippocampus through synapsin I

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