Journal
MOLECULAR PSYCHIATRY
Volume 23, Issue 2, Pages 271-281Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/mp.2016.163
Keywords
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Funding
- NIH [MH091037, MH52711, GM054051, R01MH091861, MH078833, MH101454, MH106056]
- Christopher & Dana Reeve Foundation fellowship
- Brain and Behavior Research Foundation
- New York Stem Cell Foundation
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM054051] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH052711, ZIAMH002581, R01MH091861, R01MH106056, R01MH101454, R01MH091037, U01MH078833] Funding Source: NIH RePORTER
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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 receptor (NMDAR) internalization through dephosphorylation of GluN2B and inactivation of the kinases extracellular signal-regulated kinase 1/2 and Fyn. Here we show that STEP61 is elevated in the cortex in the Nrg(1+/-) knockout mouse model of schizophrenia (SZ). Genetic reduction or pharmacological inhibition of STEP prevents the loss of NMDARs from synaptic membranes and reverses behavioral deficits in Nrg(1+/-) mice. STEP61 protein is also increased in cortical lysates from the central nervous system-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.
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