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Down‐regulation of BDNF in cell and animal models increases striatal‐enriched protein tyrosine phosphatase 61 ( STEP 61 ) levels
Author(s) -
Xu Jian,
Kurup Pradeep,
Azkona Garikoitz,
Baguley Tyler D.,
Saavedra Ana,
Nairn Angus C.,
Ellman Jonathan A.,
PérezNavarro Esther,
Lombroso Paul J.
Publication year - 2016
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13295
Subject(s) - tropomyosin receptor kinase b , brain derived neurotrophic factor , neurotrophic factors , fyn , protein tyrosine phosphatase , endocrinology , medicine , biology , synapsin i , chemistry , microbiology and biotechnology , kinase , signal transduction , tyrosine kinase , receptor , biochemistry , synaptic vesicle , vesicle , membrane
Brain‐derived neurotrophic factor ( BDNF ) regulates synaptic strengthening and memory consolidation, and altered BDNF expression is implicated in a number of neuropsychiatric and neurodegenerative disorders. BDNF potentiates N ‐methyl‐D‐aspartate receptor function through activation of Fyn and ERK 1/2. ST riatal‐Enriched protein tyrosine Phosphatase ( STEP ) is also implicated in many of the same disorders as BDNF but, in contrast to BDNF , STEP opposes the development of synaptic strengthening. STEP ‐mediated dephosphorylation of the NMDA receptor subunit GluN2B promotes internalization of GluN2B‐containing NMDA receptors, while dephosphorylation of the kinases Fyn, Pyk2, and ERK 1/2 leads to their inactivation. Thus, STEP and BDNF have opposing functions. In this study, we demonstrate that manipulation of BDNF expression has a reciprocal effect on STEP 61 levels. Reduced BDNF signaling leads to elevation of STEP 61 both in BDNF +/− mice and after acute BDNF knockdown in cortical cultures. Moreover, a newly identified STEP inhibitor reverses the biochemical and motor abnormalities in BDNF +/− mice. In contrast, increased BDNF signaling upon treatment with a tropomyosin receptor kinase B agonist results in degradation of STEP 61 and a subsequent increase in the tyrosine phosphorylation of STEP substrates in cultured neurons and in mouse frontal cortex. These findings indicate that BDNF ‐tropomyosin receptor kinase B signaling leads to degradation of STEP 61 , while decreased BDNF expression results in increased STEP 61 activity. A better understanding of the opposing interaction between STEP and BDNF in normal cognitive functions and in neuropsychiatric disorders will hopefully lead to better therapeutic strategies.Altered expression of BDNF and STEP 61 has been implicated in several neurological disorders. BDNF and STEP 61 are known to regulate synaptic strengthening, but in opposite directions. Here, we report that reduced BDNF signaling leads to elevation of STEP 61 both in BDNF +/− mice and after acute BDNF knockdown in cortical cultures. In contrast, activation of TrkB receptor results in the degradation of STEP 61 and reverses hyperlocomotor activity in BDNF +/− mice. Moreover, inhibition of STEP 61 by TC‐2153 is sufficient to enhance the Tyr phosphorylation of STEP substrates and also reverses hyperlocomotion in BDNF +/− mice. These findings give us a better understanding of the regulation of STEP 61 by BDNF in normal cognitive functions and in neuropsychiatric disorders.