Proteomic Analysis of Activity-Dependent Synaptic Plasticity in Hippocampal Neurons

Piccoli, Giovanni; Verpelli, Chiara; Tonna, Noemi; Romorini, Stefano; Alessio, Massimo; Nairn, Angus C.; Bachi, Ángela; Sala, Carlo

doi:10.1021/pr0701308

Cited by 44 publications

(45 citation statements)

References 57 publications

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Section: Resultssupporting

confidence: 89%

“…Chronic elevation of synaptic activity with BiC/4-AP for 5 d reduced dendritic spine density by 22 ± 3% (n = 36; P < 0.001) (Fig. S1B), consistent with previously described activity-dependent structural changes (21,22).To identify mRNAs that are rapidly reduced by posttranscriptional mechanisms, hippocampal neurons in culture were treated with BiC/4-AP for 5 min in the presence of the tran- …”

supporting

confidence: 86%

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MicroRNA regulation of homeostatic synaptic plasticity

Cohen

Lee

Chen

et al. 2011

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

186

163

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Homeostatic mechanisms are required to control formation and maintenance of synaptic connections to maintain the general level of neural impulse activity within normal limits. How genes controlling these processes are co-coordinately regulated during homeostatic synaptic plasticity is unknown. MicroRNAs (miRNAs) exert regulatory control over mRNA stability and translation and may contribute to local and activity-dependent posttranscriptional control of synapseassociated mRNAs. However, identifying miRNAs that function through posttranscriptional gene silencing at synapses has remained elusive. Using a bioinformatics screen to identify sequence motifs enriched in the 3′UTR of rapidly destabilized mRNAs, we identified a developmentally and activity-regulated miRNA (miR-485) that controls dendritic spine number and synapse formation in an activitydependent homeostatic manner. We find that many plasticityassociated genes contain predicted miR-485 binding sites and further identify the presynaptic protein SV2A as a target of miR-485. miR-485 negatively regulated dendritic spine density, postsynaptic density 95 (PSD-95) clustering, and surface expression of GluR2. Furthermore, miR-485 overexpression reduced spontaneous synaptic responses and transmitter release, as measured by miniature excitatory postsynaptic current (EPSC) analysis and FM 1-43 staining. SV2A knockdown mimicked the effects of miR-485, and these effects were reversed by SV2A overexpression. Moreover, 5 d of increased synaptic activity induced homeostatic changes in synaptic specializations that were blocked by a miR-485 inhibitor. Our findings reveal a role for this previously uncharacterized miRNA and the presynaptic protein SV2A in homeostatic plasticity and nervous system development, with possible implications in neurological disorders (e.g., Huntington and Alzheimer's disease), where miR-485 has been found to be dysregulated.activity-dependent development | posttranscriptional gene regulation | presynaptic terminal H omeostatic synaptic plasticity is the process of regulating synaptic connections to compensate for changes in levels of impulse activity in neural networks over a time course of days, thus maintaining circuit function within an optimal range (1). This homeostasis limits changes in synaptic strength induced by Hebbian synaptic plasticity (2), compensates for nervous system disorders causing hyper-or hypoexcitability, and adjusts excitability of neural circuits during development. How genes involved in this process are coordinately regulated is unknown.Increasing excitability of hippocampal or cortical neurons in culture using bicuculline (BiC) reduces synaptic strength through both pre-and postsynaptic mechanisms, and decreasing excitability with TTX produces the opposite response (1, 3, 4). Several molecules have been identified that contribute to homeostatic synaptic plasticity over different time scales, including alterations in the α/β Ca 2+ /CaM-dependent kinase II (CaMKII) ratio (5), astrocytic TNF-α release (6), regulation of c...

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Section: Resultssupporting

confidence: 89%

supporting

confidence: 86%

MicroRNA regulation of homeostatic synaptic plasticity

Cohen

Lee

Chen

et al. 2011

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

186

163

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“…We showed previously, using a proteomic approach, that eEF2 phosphorylation is regulated by synaptic activity in hippocampal neurons (Piccoli et al, 2007). In the present paper we show that long-term bicuculline or TTX stimulation (proxies of neuronal activity) modulate eEF2 phosphorylation and stably increase or decrease, respectively, eEF2 phosphorylation.…”

Section: Introductionsupporting

confidence: 65%

Synaptic Activity Controls Dendritic Spine Morphology by Modulating eEF2-Dependent BDNF Synthesis

Verpelli

Piccoli²,

Zibetti³

et al. 2010

J. Neurosci.

132

120

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Activity-dependent changes in synaptic structure and spine morphology are required for learning and memory, and depend on protein translation. We show that the kinase for eukaryotic elongation factor 2 (eEF2K) regulates dendritic spine stability and synaptic structure by modulating activity-dependent dendritic BDNF synthesis. Specifically RNAi knockdown of eEF2K reduces dendritic spine stability and inhibits dendritic BDNF protein expression; whereas overexpression of a constitutively activated eEF2K induces spine maturation and increases expression of dendritic BDNF. Furthermore, BDNF overexpression rescues the spine stability reduced by RNAi knockdown of eEF2K. We also show that synaptic activity-dependent spine maturation and dendritic BDNF protein expression depend on mGluR/EF2K-induced eEF2 phosphorylation. We propose that the eEF2K/eEF2 pathway is a key biochemical sensor that couple neuronal activity to spine plasticity, by controlling the dendritic translation of BDNF.

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“…These changes are bidirectional and require the activity of the UPS (18,22). It is quite plausible that neuronal activity activates regulates UPS function to control the stoichiometry of proteins at synapses.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have identified key synaptic proteins such as PSD-95, Shank, GKAP, AKAP, SPAR, RIM-1, and GRIP1 that are regulated by UPS-dependent protein turnover (10, 18 -21). In addition, it appears that cohorts of synaptic proteins are degraded in response to chronic activity blockade or up-regulation (18,22).…”

mentioning

confidence: 99%

Regulation of the Proteasome by Neuronal Activity and Calcium/Calmodulin-dependent Protein Kinase II

Djakovic

Schwarz

Baryłko

et al. 2009

Journal of Biological Chemistry

207

213

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Protein degradation via the ubiquitin proteasome system has been shown to regulate changes in synaptic strength that underlie multiple forms of synaptic plasticity. It is plausible, therefore, that the ubiquitin proteasome system is itself regulated by synaptic activity. By utilizing live-cell imaging strategies we report the rapid and dynamic regulation of the proteasome in hippocampal neurons by synaptic activity. We find that the blockade of action potentials (APs) with tetrodotoxin inhibited the activity of the proteasome, whereas the up-regulation of APs with bicuculline dramatically increased the activity of the proteasome. In addition, the regulation of the proteasome is dependent upon external calcium entry in part through N-methyl-D-aspartate receptors and L-type voltage-gated calcium channels and requires the activity of calcium/calmodulindependent protein kinase II (CaMKII). Using in vitro and in vivo assays we find that CaMKII stimulates proteasome activity and directly phosphorylates Rpt6, a subunit of the 19 S (PA700) subcomplex of the 26 S proteasome. Our data provide a novel mechanism whereby CaMKII may regulate the proteasome in neurons to facilitate remodeling of synaptic connections through protein degradation.

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Proteomic Analysis of Activity-Dependent Synaptic Plasticity in Hippocampal Neurons

Cited by 44 publications

References 57 publications

MicroRNA regulation of homeostatic synaptic plasticity

MicroRNA regulation of homeostatic synaptic plasticity

Synaptic Activity Controls Dendritic Spine Morphology by Modulating eEF2-Dependent BDNF Synthesis

Regulation of the Proteasome by Neuronal Activity and Calcium/Calmodulin-dependent Protein Kinase II

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