Striatal-Enriched tyrosine Phosphatase 61 (STEP61) is targeted to synaptic compartments and induces glutamate receptor internalization. We recently discovered that STEP61 is elevated in cingulate cortex of persons with schizophrenia (SZ). Our preliminary findings suggest that the increase of STEP61 results in internalization of glutamate receptors, a model consistent with the glutamate hypothesis of SZ. We also propose that the beneficial effects of antipsychotic medications are mediated through STEP61. The overall goals of this proposal are to define the mechanisms by which STEP61 mediates the loss of glutamate receptors in SZ, as well as its role in the beneficial effects of neuroleptics.
In Aim 1, we will increase our samples of SZ cingulate cortex and include dorsolateral PFC. Our prediction is that STEP61 will again be elevated. We will determine the molecular mechanism by which this occurs. STEP61 is normally ubiquitinated and degraded by the proteasome. We propose that this process is disrupted in SZ. PKA phosphorylation of STEP61 is one signal that is necessary for the ubiquitination of STEP61. In the absence of PKA-phosphorylation, STEP61 is no longer ubiquitinated and degraded. We hypothesize, however, that additional kinases are required, and will identify these kinases and their phosphorylation sites in STEP61.
Aim 1 will also test the hypothesis that the beneficial effects of neuroleptics are mediated through STEP61. We predict that dopamine D2R antagonists activate PKA, leading to the phosphorylation and inactivation of STEP61. Inactivation of STEP61 promotes trafficking of NMDAR to neuronal membranes.
Aim 1 is significant as it explains aspects of the glutamate hypothesis of SZ as well as how neuroleptics function to ameliorate symptoms.
Aim 2 will test our hypothesis in an animal model of SZ (NRG1 mice). NRG1 mice have decreased functional NMDARs on neuronal surfaces. Our hypothesis is that the loss of these receptors is mediated by activation of STEP61. We will first test our hypothesis by stimulating neuronal cultures and slices derived from WT and STEP KO mice with NRG1. Our prediction is that the absence of STEP61 will prevent NRG1-induced internalization of NMDARs. We will also test our hypothesis by crossing NRG1 with STEP KO mice. We predict that progeny null for STEP will rescue the loss of NMDARs from neuronal membranes. STEP KO mice have elevated levels of NMDARs and AMPARs on neuronal membranes.
Aim 3 will test the hypothesis that these mice are less sensitive to the effects of psychotomimetic agents. Preliminary data indicate that this is the case: STEP KO mice are less sensitive to the acute effects of PCP on locomotor activity, as well as the subchronic effects of PCP on cognition. We have developed a STEP inhibitor called LDN-33960, and have shown that this compound reduces the acute effects of PCP on locomotor activity. We will test if this compound also reduces the cognitive deficits induced by PCP. Ultimately, our work has the potential of discovering a new family of therapeutic agents for SZ.

Public Health Relevance

This R01 proposes a new hypothesis in the field of Schizophrenia Research: it implicates STriatal-Enriched tyrosine Phosphatase (STEP) in the pathophysiology of this devastating disease through STEP's ability to promote NMDAR internalization. STEP KO mice are less sensitive to the psychotomimetic effects of the noncompetitive NMDAR antagonist, PCP, and proof-of-concept studies demonstrate that a STEP inhibitor we have developed reduces the effects of PCP in WT mice. The proposed studies have the potential of making a major advance in the field as we will clarify how neuroleptics function, and we will also determine how the neuregulin/ErbB4 pathway, which has been implicated in the disease in genetic studies of schizophrenia, exerts its effects through STEP.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Meinecke, Douglas L
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Yale University
Schools of Medicine
New Haven
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Xu, Jian; Kurup, Pradeep; Baguley, Tyler D et al. (2016) Inhibition of the tyrosine phosphatase STEP61 restores BDNF expression and reverses motor and cognitive deficits in phencyclidine-treated mice. Cell Mol Life Sci 73:1503-14
Xu, Jian; Kurup, Pradeep; Azkona, Garikoitz et al. (2016) Down-regulation of BDNF in cell and animal models increases striatal-enriched protein tyrosine phosphatase 61 (STEP61 ) levels. J Neurochem 136:285-94
Azkona, Garikoitz; Saavedra, Ana; Aira, Zigor et al. (2016) Striatal-enriched protein tyrosine phosphatase modulates nociception: evidence from genetic deletion and pharmacological inhibition. Pain 157:377-86
Saavedra, Ana; PuigdellĂ­vol, Mar; Tyebji, Shiraz et al. (2016) BDNF Induces Striatal-Enriched Protein Tyrosine Phosphatase 61 Degradation Through the Proteasome. Mol Neurobiol 53:4261-4273
Xu, Jian; Kurup, Pradeep; Foscue, Ethan et al. (2015) Striatal-enriched protein tyrosine phosphatase regulates the PTP?/Fyn signaling pathway. J Neurochem 134:629-41
Jang, Sung-Soo; Royston, Sara E; Xu, Jian et al. (2015) Regulation of STEP61 and tyrosine-phosphorylation of NMDA and AMPA receptors during homeostatic synaptic plasticity. Mol Brain 8:55
Kurup, Pradeep K; Xu, Jian; Videira, Rita Alexandra et al. (2015) STEP61 is a substrate of the E3 ligase parkin and is upregulated in Parkinson's disease. Proc Natl Acad Sci U S A 112:1202-7
Pellman, Jessica J; Hamilton, James; Brustovetsky, Tatiana et al. (2015) Ca(2+) handling in isolated brain mitochondria and cultured neurons derived from the YAC128 mouse model of Huntington's disease. J Neurochem 134:652-67
Karasawa, Takatoshi; Lombroso, Paul J (2014) Disruption of striatal-enriched protein tyrosine phosphatase (STEP) function in neuropsychiatric disorders. Neurosci Res 89:1-9
Ng, Ai Na; Doherty, Andrew J; Lombroso, Paul J et al. (2014) Rapid regulation of endoplasmic reticulum dynamics in dendritic spines by NMDA receptor activation. Mol Brain 7:60

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