Abstract
Glutamatergic signaling through N-methyl-D-aspartate receptors (NMDARs) is required for synaptic plasticity. Disruptions in glutamatergic signaling are proposed to contribute to the behavioral and cognitive deficits observed in schizophrenia (SZ). One possible source of compromised glutamatergic function in SZ is decreased surface expression of GluN2B-containing NMDARs. STEP61 is a brain-enriched protein tyrosine phosphatase that dephosphorylates a regulatory tyrosine on GluN2B, thereby promoting its internalization. Here, we report that STEP61 levels are significantly higher in the postmortem anterior cingulate cortex and dorsolateral prefrontal cortex of SZ patients, as well as in mice treated with the psychotomimetics MK-801 and phencyclidine (PCP). Accumulation of STEP61 after MK-801 treatment is due to a disruption in the ubiquitin proteasome system that normally degrades STEP61. STEP knockout mice are less sensitive to both the locomotor and cognitive effects of acute and chronic administration of PCP, supporting the functional relevance of increased STEP61 levels in SZ. In addition, chronic treatment of mice with both typical and atypical antipsychotic medications results in a protein kinase A-mediated phosphorylation and inactivation of STEP61 and, consequently, increased surface expression of GluN1/GluN2B receptors. Taken together, our findings suggest that STEP61 accumulation may contribute to the pathophysiology of SZ. Moreover, we show a mechanistic link between neuroleptic treatment, STEP61 inactivation and increased surface expression of NMDARs, consistent with the glutamate hypothesis of SZ.
Highlights
We again observed a significant increase in STEP61 in the dorsolateral prefrontal cortex (DLPFC) of SZ subjects using sex, age and PMI as covariates (Po0.05; Figures 1c and d), and there was no influence of the covariates on the main effect
As increased STEP61 activity leads to loss of GluN2B-containing N-methyl-D-aspartate receptors (NMDARs) from neuronal membrane surfaces, we investigated whether antipsychotic medications exert their beneficial effects by inactivating STEP61
Positron emission tomography scans suggest that hippocampal NMDAR binding is significantly reduced in untreated, but not antipsychotic-treated, SZ patients.[66]
Summary
Hypofunction of N-methyl-D-aspartate receptors (NMDARs), is proposed as a contributing factor in the etiology of schizophrenia (SZ).[1,2,3] Several neuropathological studies show abnormal glutamate receptor densities in the prefrontal cortex, thalamus and temporal lobe, as well as decreased receptor function in SZ brains.[4,5] Noncompetitive NMDAR antagonists such as phencyclidine (PCP) and ketamine elicit SZ-like symptoms in normal individuals and exacerbate psychotic episodes in SZ patients;[2,3,6,7] and administration of these psychotomimetics, or the more selective NMDAR antagonist MK-801, is used to model SZ in rodents and primates. The STEP gene is alternatively spliced to produce several isoforms with domains that regulate their localization, substrate specificity and activity.[23,24,25] STEP61 is associated with postsynaptic densities in the striatum, cortex, hippocampus and related regions.[26,27,28] Substrates include the NMDAR subunit GluN2B,29,30 the AMPA receptor subunit GluA2,31 Fyn,[32] Pyk[2,33,34] and the MAPK proteins ERK1/2 and p38.35,36
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