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 ERK1/2. STriatal-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 ERK1/2 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 STEP61 levels. Reduced
BDNF signaling leads to elevation of STEP61 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 STEP61 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 STEP61 , while decreased
BDNF expression results in increased STEP61 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 STEP61 has been implicated in several
neurological disorders.
BDNF and STEP61 are known to regulate synaptic strengthening, but in opposite directions. Here, we report that reduced
BDNF signaling leads to elevation of STEP61 both in
BDNF(+/-) mice and after acute
BDNF knockdown in cortical cultures. In contrast, activation of
TrkB receptor results in the degradation of STEP61 and reverses hyperlocomotor activity in
BDNF(+/-) mice. Moreover, inhibition of STEP61 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 STEP61 by
BDNF in normal cognitive functions and in neuropsychiatric disorders.