Inhibition of the tyrosine phosphatase STEP61 restores BDNF expression and reverses motor and cognitive deficits in phencyclidine-treated mice

• Published in: Cellular and molecular life sciences : CMLS 2016-04, Vol.73 (7), p.1503-1514
• Main Authors: Xu, Jian, Kurup, Pradeep, Baguley, Tyler D., Foscue, Ethan, Ellman, Jonathan A., Nairn, Angus C., Lombroso, Paul J.
• Format: Article
• Language: English
• Subjects: Animals; Benzothiepins - pharmacology; Biochemistry; Biomedical and Life Sciences; Biomedicine; Brain-Derived Neurotrophic Factor - analysis; Brain-Derived Neurotrophic Factor - metabolism; Cell Biology; Cells, Cultured; Cognition Disorders - drug therapy; Cognition Disorders - metabolism; Cognition Disorders - pathology; CREB-Binding Protein - antagonists & inhibitors; CREB-Binding Protein - genetics; CREB-Binding Protein - metabolism; Down-Regulation - drug effects; Life Sciences; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Motor Activity - drug effects; Neurons - cytology; Neurons - metabolism; Original Article; Phencyclidine - pharmacology; Phencyclidine - therapeutic use; Phosphorylation - drug effects; Protein Tyrosine Phosphatases - antagonists & inhibitors; Protein Tyrosine Phosphatases - genetics; Protein Tyrosine Phosphatases - metabolism; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; RNA Interference; Ubiquitination
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-015-2057-1

Brain-derived neurotrophic factor (BDNF) and STriatal-Enriched protein tyrosine Phosphatase 61 (STEP 61 ) have opposing functions in the brain, with BDNF supporting and STEP 61 opposing synaptic strengthening. BDNF and STEP 61 also exhibit an inverse pattern of expression in a number of brain disorders, including schizophrenia (SZ). NMDAR antagonists such as phencyclidine (PCP) elicit SZ-like symptoms in rodent models and unaffected individuals, and exacerbate psychotic episodes in SZ. Here we characterize the regulation of BDNF expression by STEP 61 , utilizing PCP-treated cortical culture and PCP-treated mice. PCP-treated cortical neurons showed both an increase in STEP 61 levels and a decrease in BDNF expression. The reduction in BDNF expression was prevented by STEP 61 knockdown or use of the STEP inhibitor, TC-2153. The PCP-induced increase in STEP 61 expression was associated with the inhibition of CREB-dependent BDNF transcription. Similarly, both genetic and pharmacologic inhibition of STEP prevented the PCP-induced reduction in BDNF expression in vivo and normalized PCP-induced hyperlocomotion and cognitive deficits. These results suggest a mechanism by which STEP 61 regulates BDNF expression, with implications for cognitive functioning in CNS disorders.