Inhibition of the tyrosine phosphatase STEP61 restores BDNF expression and reverses motor and cognitive deficits in phencyclidine-treated mice.
Cellular and molecular life sciences : CMLS April 1, 2016 Jian Xu, Pradeep Kurup, Tyler D Baguley et al.
BDNF and STEP61 have opposing roles in the brain, with BDNF supporting synaptic strengthening and STEP61 opposing it. In schizophrenia and related disorders, their expression is often inversely related. Treating cortical neurons or mice with the NMDAR antagonist phencyclidine (PCP), which elicits schizophrenia-like symptoms, increased STEP61 levels and decreased BDNF expression. Reducing STEP61, either by knockdown or with the inhibitor TC-2153, prevented the drop in BDNF. The increase in STEP61 inhibited CREB-dependent BDNF transcription. In mice, genetic or pharmacological inhibition of STEP prevented PCP-induced reductions in BDNF and normalized hyperlocomotion and cognitive deficits. The findings suggest a mechanism linking STEP61 to BDNF regulation, with relevance to cognitive dysfunction in central nervous system disorders.