Regulation of Synaptic Strength by Protein Phosphatase 1

Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
Neuron (Impact Factor: 15.05). 01/2002; 32(6):1133-48. DOI: 10.1016/S0896-6273(01)00554-2
Source: PubMed


We investigated the role of postsynaptic protein phosphatase 1 (PP1) in regulating synaptic strength by loading CA1 pyramidal cells either with peptides that disrupt PP1 binding to synaptic targeting proteins or with active PP1. The peptides blocked synaptically evoked LTD but had no effect on basal synaptic currents mediated by either AMPA or NMDA receptors. They did, however, cause an increase in synaptic strength following the induction of LTD. Similarly, PP1 had no effect on basal synaptic strength but enhanced LTD. In cultured neurons, synaptic activation of NMDA receptors increased the proportion of PP1 localized to synapses. These results suggest that PP1 does not significantly regulate basal synaptic strength. Appropriate NMDA receptor activation, however, allows PP1 to gain access to synaptic substrates and be recruited to synapses where its activity is necessary for sustaining LTD.

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Available from: Houhui Xia, May 22, 2014
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    • "In contrast, long-term depression (LTD), a form of synaptic weakening, requires a moderate rise of intracellular calcium concentration that activates protein phosphatases including PP2B (calcineurin) and subsequently PP1 (Mulkey et al., 1993, 1994; Jouvenceau et al., 2003, 2006; Pi and Lisman, 2008). Once activated, PP1 dephosphorylates some of its targets in synaptic terminals (Morishita et al., 2001), in particular, post-synaptic NMDAR and AMPAR subunits, leading to NMDAR downregulation and AMPAR endocytosis, ultimately resulting in synaptic depression [for review, see (Mansuy and Shenolikar, 2006)]. "
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    ABSTRACT: Citation: Mirante O, Brandalise F, Bohacek J and Mansuy IM(2014) Distinct molecular components for thalamic-and cortical-dependent plasticity in the lateral amygdala. Front. Mol. Neurosci. 7:62. doi:10.3389/fnmol.2014.00062 /Journal/Abstract.aspx?s=702& name=molecular%20neuroscience& ART_DOI=10.3389/fnmol.2014.00062: /Journal/Abstract.aspx?s=702& name=molecular%20neuroscience&ART_DOI=10.3389 /fnmol.2014.00062 (If clicking on the link doesn't work, try copying and pasting it into your browser.) Copyright statement: © 2014 Mirante, Brandalise, Bohacek and Mansuy. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. This Provisional PDF corresponds to the article as it appeared upon acceptance, after rigorous peer-review. Fully formatted PDF and full text (HTML) versions will be made available soon.
    Full-text · Article · Jun 2014 · Frontiers in Molecular Neuroscience
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    • "Perhaps due to their unique subcellular localization, i.e., extrasynaptic (Bliss and Schoepfer, 2004; which is yet to be confirmed in the PFC by ultrastructural studies), GluN2B-NMDARs have been considered especially suitable for detection of post–pre spiking pairs, transducing negatively correlated synaptic activity patterns to LTD (Gerkin et al., 2007). Compared to GluN2A-NMDARs, GluN2B-NMDARs undergo a slower Mg2+ unblockade by back-propagating APs (bAPs; Clarke and Johnson, 2006), have a lower open channel probability (Chen et al., 1999), and permit less Ca2+ influx, favoring the induction of LTD possibly by activating protein phosphatases 1 (PP1) and 2B (PP2B/calcineurin; Mulkey et al., 1994; Morishita et al., 2001). DA can inhibit PP1 and activate CaMKII, an essential signaling molecule required for most forms of LTP (Malenka and Bear, 2004), in the synapse through the D1R-cAMP/PKA-Inhibitor I/DARPP-32 pathway (Greengard et al., 1999), thus converting a “would-be-LTD” elicited by negative timing stimuli to LTP. "
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    ABSTRACT: Spike timing-dependent plasticity (STDP) of glutamatergic synapses is a Hebbian associative plasticity that may underlie certain forms of learning. A cardinal feature of STDP is its dependence on the temporal order of presynaptic and postsynaptic spikes during induction: pre-post (positive) pairings induce t-LTP (timing-dependent long-term potentiation) whereas post-pre (negative) pairings induce t-LTD (timing-dependent long-term depression). Dopamine (DA), a reward signal for behavioral learning, is believed to exert powerful modulations on synapse strength and plasticity, but its influence on STDP has remained incompletely understood. We previously showed that DA extends the temporal window of t-LTP in the prefrontal cortex (PFC) from +10 to +30 ms, gating Hebbian t-LTP. Here, we examined DA modulation of synaptic plasticity induced at negative timings in layer V pyramidal neurons on mouse medial PFC slices. Using a negative timing STDP protocol (60 post-pre pairings at 0.1 Hz, δt = -30 ms), we found that DA applied during post-pre pairings did not produce LTD, but instead enabled robust LTP. This anti-Hebbian t-LTP depended on GluN2B-containing NMDA receptors. Blocking D1- (D1Rs), but not D2- (D2Rs) class DA receptors or disrupting cAMP/PKA signaling in pyramidal neurons also abolished this atypical t-LTP, indicating that it was mediated by postsynaptic D1R-cAMP/PKA signaling in excitatory synapses. Unlike DA-enabled Hebbian t-LTP that requires suppression of GABAergic inhibition and cooperative actions of both D1Rs and D2Rs in separate PFC excitatory and inhibitory circuits, DA-enabled anti-Hebbian t-LTP occurred under intact inhibitory transmission and only required D1R activation in excitatory circuit. Our results establish DA as a potent modulator of coincidence detection during associative synaptic plasticity and suggest a mechanism by which DA facilitates input-target association during reward learning and top-down information processing in PFC circuits.
    Full-text · Article · Apr 2014 · Frontiers in Neural Circuits
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    • "Because of the pharmacological and molecular-genetic limitations of studying phosphatases, we cannot rule out a contribution of PP2A to the dephosphorylation of Sp4; however, our data strongly implicate the activity of PP1. PP1 has been shown to specifically contribute to certain forms of NMDA receptor-dependent long-term depression (Mulkey et al. 1994; Morishita et al. 2001; Genoux et al. 2002). NMDA receptor activation of PP1 is often observed in response to stimulation paradigms that activate long-term depression and require calcineurin activation. "
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    ABSTRACT: The regulation of transcription factor function in response to neuronal activity is important for development and function of the nervous system. The transcription factor Sp4 regulates the developmental patterning of dendrites, contributes to complex processes including learning and memory, and has been linked to psychiatric disorders such as schizophrenia and bipolar disorder. Despite its many roles in the nervous system, the molecular mechanisms regulating Sp4 activity are poorly understood. Here, we report a site of phosphorylation on Sp4 at serine 770 that is decreased in response to membrane depolarization. Inhibition of the voltage-dependent NMDA receptor increased Sp4 phosphorylation. Conversely, stimulation with NMDA reduced the levels of Sp4 phosphorylation, and this was dependent on the protein phosphatase 1/2A (PP1/PP2A). A phospho-mimetic substitution at S770 impaired the Sp4-dependent maturation of cerebellar granule neuron primary dendrites, whereas a non-phosphorylatable Sp4 mutant behaved like wild-type. These data reveal that transcription factor Sp4 is regulated by NMDA receptor-dependent activation of a PP1/PP2A signaling pathway. Our findings also suggest that the regulated control of Sp4 activity is an important mechanism governing the developmental patterning of dendrites. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jan 2014 · Journal of Neurochemistry
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