The tyrosine phosphatase STEP: Implications in schizophrenia and the molecular mechanism underlying antipsychotic medications

Child Study Center, Yale University School of Medicine, New Haven, CT 06520-7900, USA.
Translational Psychiatry (Impact Factor: 5.62). 07/2012; 2(7):e137. DOI: 10.1038/tp.2012.63
Source: PubMed


Glutamatergic signaling through N-methyl-D-aspartate receptors (NMDARs) is required for synaptic plasticity. Disruptions in glutamatergic signaling are proposed to contribute to the behavioral and cognitive deficits observed in schizophrenia (SZ). One possible source of compromised glutamatergic function in SZ is decreased surface expression of GluN2B-containing NMDARs. STEP(61) is a brain-enriched protein tyrosine phosphatase that dephosphorylates a regulatory tyrosine on GluN2B, thereby promoting its internalization. Here, we report that STEP(61) levels are significantly higher in the postmortem anterior cingulate cortex and dorsolateral prefrontal cortex of SZ patients, as well as in mice treated with the psychotomimetics MK-801 and phencyclidine (PCP). Accumulation of STEP(61) after MK-801 treatment is due to a disruption in the ubiquitin proteasome system that normally degrades STEP(61). STEP knockout mice are less sensitive to both the locomotor and cognitive effects of acute and chronic administration of PCP, supporting the functional relevance of increased STEP(61) levels in SZ. In addition, chronic treatment of mice with both typical and atypical antipsychotic medications results in a protein kinase A-mediated phosphorylation and inactivation of STEP(61) and, consequently, increased surface expression of GluN1/GluN2B receptors. Taken together, our findings suggest that STEP(61) accumulation may contribute to the pathophysiology of SZ. Moreover, we show a mechanistic link between neuroleptic treatment, STEP(61) inactivation and increased surface expression of NMDARs, consistent with the glutamate hypothesis of SZ.

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    • "Carty et al. (2012) found that chronic (three-week) treatment with haloperidol, clozapine, or risperidone increased phosphorylation of STEP 61 kDa, which leads to its inactivation. However, they found no impact of antipsychotics on STEP 61 kDa mRNA or protein levels (Carty et al., 2012). Thus, it is unlikely that our reported changes in schizophrenia are due to antipsychotic treatment. "
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    ABSTRACT: Fragile X mental retardation protein (FMRP) is an RNA binding protein with 842 target mRNAs in mammalian brain. Silencing of the fragile X mental retardation 1 (FMR1) gene leads to loss of expression of FMRP and upregulated metabotropic glutamate receptor 5 (mGluR5) signaling resulting in the multiple physical and cognitive deficits associated with fragile X syndrome (FXS). Reduced FMRP expression has been identified in subjects with autism, schizophrenia, bipolar disorder, and major depression who do not carry the mutation for FMR1. Our laboratory has recently demonstrated altered expression of four downstream targets of FMRP-mGluR5 signaling in brains of subjects with autism: homer 1, amyloid beta A4 precursor protein (APP), ras-related C3 botulinum toxin substrate 1 (RAC1), and striatal-enriched protein tyrosine phosphatase (STEP). In the current study we investigated the expression of the same four proteins in lateral cerebella of subjects with schizophrenia, bipolar disorder, and major depression and in frontal cortex of subjects with schizophrenia and bipolar disorder. In frontal cortex we observed: 1) reduced expression of 120kDa form of APP in subjects with schizophrenia and bipolar disorder; 2) reduced expression of 61kDa and 33kDa forms of STEP in subjects with schizophrenia; 3) reduced expression of 88kDa form of APP in subjects with bipolar disorder; and 3) trends for reduced expression of 88kDa form of APP and homer 1 in subjects with schizophrenia and bipolar disorder, respectively. In lateral cerebella there was no group difference, however we observed increased expression of RAC1 in subjects with bipolar disorder, and trends for increased RAC1 in subjects with schizophrenia and major depression. Our results provide further evidence that proteins involved in the FMRP-mGluR5 signaling pathway are altered in schizophrenia and mood disorders. Copyright © 2015 Elsevier B.V. All rights reserved.
    Schizophrenia Research 05/2015; 165(2-3). DOI:10.1016/j.schres.2015.04.012 · 3.92 Impact Factor
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    • "Recent investigations have implicated STEP in the etiology of neuropsychiatric disorders [74]. Carty et al. [75] reported significant increases in STEP 61 kDa in the anterior cingulate and dorsolateral prefrontal cortices of subjects with schizophrenia. STEP has roles in mediating NMDA and AMPA receptor endocytosis [70,76], suggesting that it has a role in mGluR5-mediated long-term depression (LTD), a phenomenon that is enhanced in Fmr1 KO mice [77]. "
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