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

Abstract

Brain-derived neurotrophic factor (BDNF) and STriatal-Enriched protein tyrosine Phosphatase 61 (STEP61) have opposing functions in the brain, with BDNF supporting and STEP61 opposing synaptic strengthening. BDNF and STEP61 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 STEP61, utilizing PCP-treated cortical culture and PCP-treated mice. PCP-treated cortical neurons showed both an increase in STEP61 levels and a decrease in BDNF expression. The reduction in BDNF expression was prevented by STEP61 knockdown or use of the STEP inhibitor, TC-2153. The PCP-induced increase in STEP61 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 STEP61 regulates BDNF expression, with implications for cognitive functioning in CNS disorders.

Intra‐prelimbic cortical inhibition of striatal‐enriched tyrosine phosphatase suppresses cocaine seeking in rats

“…TC‐2153 treatment reverses the biochemical, electrophysiological and cognitive deficits in mouse models of schizophrenia and in glutamatergic neurons derived from human‐induced pluripotent stem cells from schizophrenic patients (Xu et al ). As expected, TC‐2153 acutely increases ERK phosphorylation in vivo (Xu et al ,b).…”

“…For example, STEP activity is elevated in human post‐mortem samples and in animal models of Alzheimer's disease (Snyder et al ; Kurup et al ), Parkinson's disease (Kurup et al ) and schizophrenia (Xu et al ). Moreover, inhibition of STEP with systemic injections of the novel, relatively selective inhibitor, TC‐2153, significantly improves memory deficits in a mouse model of Alzheimer's disease (Xu et al ) as well as phencyclidine‐induced hyperlocomotion in mice (Xu et al ). TC‐2153 treatment reverses the biochemical, electrophysiological and cognitive deficits in mouse models of schizophrenia and in glutamatergic neurons derived from human‐induced pluripotent stem cells from schizophrenic patients (Xu et al ).…”

Inhibition of STEP61 ameliorates deficits in mouse and hiPSC-based schizophrenia models

“…Our previous findings 12, 38 suggested that genetic reduction of STEP was sufficient to reduce the biochemical and behavioral changes induced by the NMDAR antagonist PCP. To further demonstrate that pharmacological inhibition of STEP was sufficient to ameliorate the behavioral effects arising from NMDAR antagonism, we used another NMDAR blocker, MK-801, which has been widely validated as a pharmacological model of SZ and induces motor and cognitive deficits in mice 39-41 .…”

Covalent inhibition of protein tyrosine phosphatases

“…154 In vitro selectivity experiments on full length PTPs revealed that TC-2153 is more potent on isoforms of STEP, STEP 46 (IC 50 = 57 nM) and STEP 61 (IC 50 = 93 nM), compared to highly related PTPs, PTP-SL (IC 50 = 220 nM), and HePTP (IC 50 = 363 nM). It showed even greater selectivity over SHP2 (IC 50 = 6,896 nM) and PTP1B (IC 50 = 723 nM).…”