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

Abstract

The brain-specific tyrosine phosphatase, STEP (STriatal-Enriched protein tyrosine Phosphatase) is an important regulator of synaptic function. STEP normally opposes synaptic strengthening by increasing N-methyl D-aspartate glutamate receptors (NMDARs) internalization through dephosphorylation of GluN2B and inactivation of the kinases ERK1/2 and Fyn. Here we show that STEP61 is elevated in the cortex in the Nrg1+/− knockout mouse model of SZ. Genetic reduction or pharmacological inhibition of STEP prevents the loss of NMDA receptors from synaptic membranes and reverses behavioral deficits in Nrg1+/− mice. STEP61 protein is also increased in cortical lysates from the CNS-specific ErbB2/4 mouse model of SZ, as well as in human induced pluripotent stem cell (hiPSC)-derived forebrain neurons and Ngn2-induced excitatory neurons from two independent SZ patient cohorts. In these selected SZ models, increased STEP61 protein levels likely reflect reduced ubiquitination and degradation. These convergent findings from mouse and hiPSC SZ models provide evidence for STEP61 dysfunction in SZ.

Application of induced pluripotent stem cells to understand neurobiological basis of bipolar disorder and schizophrenia

“…Another iPSC‐studied synapse‐regulating protein is striatal‐enriched protein tyrosine phosphatase (STEP), which acts to increase NMDAR internalization through dephosphorylating GluN2B and ERK1/2 to baffle synaptic potentiation. Xu et al recently reported that STEP 61 , one isoform of STEP, was elevated in SCZD patient iPSC‐derived forebrain neurons and induced excitatory neurons, which is consistent with their observation in the cortical lysates of the Nrg1 +/− mouse model of SCZD. Treating the iPSC‐derived neurons with neuroleptics would inhibit STEP activity, which consequently increased the phosphorylation of GluN2B and ERK1/2.…”

Targeting Tyrosine Phosphatases: Time to End the Stigma

“…In vivo TC-2153 administration caused increased ERK1/2 and Pyk2 phosphorylation only in brain tissues expressing STEP, and improved novel object recognition and reference memory in the 3xTg-AD model. TC-2153 treatment also improved cognitive and motor function in the phencyclidine-induced mouse model of schizophrenia[34]. …”

Protein phosphatase 2A and tau: an orchestrated ‘Pas de Deux’

“…There, PP2A functionally associates with NR3 subunit‐containing NMDAR complexes . PP2A dissociates in a catalytically inactive state from these particular complexes following NMDAR activation (Fig. ).…”