Synaptic plasticity: one STEP at a time

AGY Therapeutics Inc., 270 E. Grand Avenue, South San Francisco, CA 94080, USA.
Trends in Neurosciences (Impact Factor: 13.56). 09/2006; 29(8):452-8. DOI: 10.1016/j.tins.2006.06.007
Source: PubMed


Striatal enriched tyrosine phosphatase (STEP) has recently been identified as a crucial player in the regulation of synaptic function. It is restricted to neurons within the CNS and acts by downregulating the activity of MAP kinases, the tyrosine kinase Fyn and NMDA receptors. By modulating these substrates, STEP acts on several parallel pathways that impact upon the progression of synaptic plasticity. Here, we review recent advances that demonstrate the importance of STEP in normal cognitive function, and its possible involvement in cognitive disorders such as Alzheimer's disease.

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Available from: Paul Lombroso, Oct 07, 2014
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    • "This finding is in accord with our previous study demonstrating that motor learning induces genes expression [7]. The current proposed molecular model is that STEP activation acts as a tonic brake on synaptic transmission, which is associated with a decline in memory function [37]–[39]. Dephosphorylation of STEP increases its activity that will, in turn, inactivates key signaling molecules reinforcing synaptic plasticity, such as extracellular signal-regulated kinase 1/2 (ERK1/2) or NR2B subunit of N-methyl-D-aspartate receptors (NMDARs) [23], [40], [41]. In accord with this contention, STEP inhibition in CA1 hippocampal neurons enhanced transmission and occluded LTP induction [42]. "
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    ABSTRACT: Recently, striatal-enriched protein tyrosine phosphatase (STEP) and its upstream regulator protein kinase A (PKA) have been suspected to play a role in the intracellular mechanisms of fear conditioning and spatial memory. However, whether they contribute to the learning and memory of motor skills is totally unknown. In this study, we have investigated the role of STEP and PKA activities during motor skill learning associated with the accelerating rotarod task. We observed that learning the rotarod task differentially modulated the levels of phosphorylated STEP61 at serine 221, a site directly regulated by PKA, in the hippocampus, motor cortex and striatum. In a second set of experiments, we have pharmacologically inhibited PKA by the injection of Rp-cAMPS directly into the dorsal striatum of mice before rotarod trainings. PKA phosphorylation of STEP prevents the dephosphorylation of STEP substrates, whereas inhibition of PKA promotes STEP activity. Striatal PKA inhibitions dose-dependently impaired mice performances on the accelerating rotarod task. General motor abilities testing revealed an intact motor control in mice treated with 5 and 20 µg of Rp-cAMPS, but not at the highest dose of 40 µg. This suggested that motor learning was selectively affected by PKA inhibition at lower doses. Most notably, striatal inhibition of PKA reduced the levels of phosphorylated STEP61 at serine 221. Our data support that inactivation of STEP61 by the PKA activity is part of the molecular process associated with motor skill learning.
    PLoS ONE 01/2014; 9(1):e86988. DOI:10.1371/journal.pone.0086988 · 3.23 Impact Factor
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    • "Thus, A b would ultimately reduce GluN2B phosphorylation at a regulatory tyrosine (1472) site, which is responsible for controlling the traf fi cking of NMDARs to the cell surface (Snyder et al. 2005 ) . The ultimate effect of A b is to decrease surface expression of GluN2B by both reduced exocytosis and enhanced endocytosis of this subunit (Braithwaite et al. 2006 ; Nguyen et al. 2002 ; Paul et al. 2003 ; Snyder et al. 2005 ) . Acute applications of A b also decreased the amplitude of NMDAR-mediated currents in cultured neurons (Snyder et al. 2005 ) . "
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    ABSTRACT: Stroke is a very strong risk factor for dementia. Furthermore, ischemic stroke and Alzheimer's disease (AD) share a number of overlapping mechanisms of neuron loss and dysfunction, including those induced by the inappropriate activation of N-methyl-D-aspartate receptors (NMDARs). These receptors form a major subtype of excitatory glutamate receptor. They are nonselective cation channels with appreciable Ca(2+) permeability, and their overactivation leads to neurotoxicity in the cortex and hippocampus. NMDARs have therefore been therapeutic targets in both conditions, but they have failed in the treatment of stroke, and there is limited rationale for using them in treating AD. In this chapter, we discuss current understanding of subtypes of NMDARs and their potential roles in -ischemic stroke and AD. We also discuss the properties of several other nonselective cation channels, transient receptor potential melastatin 2 and 7 channels, and their implications in linking these conditions.
    Advances in Experimental Medicine and Biology 01/2013; 961:433-47. DOI:10.1007/978-1-4614-4756-6_37 · 1.96 Impact Factor
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    • "Third, synapses in mice lacking FMRP could have suppressed NMDA receptor currents due to post-translational modifications of the receptors themselves or differences in the synaptic micro-environment of the PSD. Multiple kinases and phosphatases interact with C-terminal tails of synaptic NMDA receptors and associated molecular ensembles (MacDonald et al., 1989; Kelso et al., 1992; Tingley et al., 1993; Wang and Salter, 1994; Salter and Kalia, 2004; Braithwaite et al., 2006; Skeberdis et al., 2006) and phosphorylation state can influence channel gating kinetics (Yu et al., 1997; Lan et al., 2001; Krupp et al., 2002; Jones and Leonard, 2005). The absence of significant differences in decay kinetics of NMDA receptor-mediated currents between WT and Fmr1-KO mice does not support this mechanism. "
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    ABSTRACT: Fragile X syndrome is a neurodevelopmental condition caused by the transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene. The Fmr1 knockout (KO) mouse exhibits age-dependent deficits in long term potentiation (LTP) at association (ASSN) synapses in anterior piriform cortex (APC). To investigate the mechanisms for this, whole-cell voltage-clamp recordings of ASSN stimulation-evoked synaptic currents were made in APC of slices from adult Fmr1-KO and wild-type (WT) mice, using the competitive N-methyl-D-aspartate (NMDA) receptor antagonist, CPP, to distinguish currents mediated by NMDA and AMPA receptors. NMDA/AMPA current ratios were lower in Fmr1-KO mice than in WT mice, at ages ranging from 3-18months. Since amplitude and frequency of miniature excitatory postsynaptic currents (mEPSCs) mediated by AMPA receptors were no different in Fmr1-KO and WT mice at these ages, the results suggest that NMDA receptor-mediated currents are selectively reduced in Fmr1-KO mice. Analyses of voltage-dependence and decay kinetics of NMDA receptor-mediated currents did not reveal differences between Fmr1-KO and WT mice, suggesting that reduced NMDA currents in Fmr1-KO mice are due to fewer synaptic receptors rather than differences in receptor subunit composition. Reduced NMDA receptor signaling may help to explain the LTP deficit seen at APC ASSN synapses in Fmr1-KO mice at 6-18months of age, but does not explain normal LTP at these synapses in mice 3-6months old. Evoked currents and mEPSCs were also examined in senescent Fmr1-KO and WT mice at 24-28months of age. NMDA/AMPA ratios were similar in senescent WT and Fmr1-KO mice, due to a decrease in the ratio in the WT mice, without significant change in AMPA receptor-mediated mEPSCs.
    Neuroscience 06/2012; 221:170-81. DOI:10.1016/j.neuroscience.2012.06.052 · 3.36 Impact Factor
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