Role of Striatal-Enriched Tyrosine Phosphatase in Neuronal Function

Abstract

Striatal-enriched protein tyrosine phosphatase (STEP) is a CNS-enriched protein implicated in multiple neurologic and neuropsychiatric disorders. STEP regulates key signaling proteins required for synaptic strengthening as well as NMDA and AMPA receptor trafficking. Both high and low levels of STEP disrupt synaptic function and contribute to learning and behavioral deficits. High levels of STEP are present in human postmortem samples and animal models of Alzheimer's disease, Parkinson's disease, and schizophrenia and in animal models of fragile X syndrome. Low levels of STEP activity are present in additional disorders that include ischemia, Huntington's chorea, alcohol abuse, and stress disorders. Thus the current model of STEP is that optimal levels are required for optimal synaptic function. Here we focus on the role of STEP in Alzheimer's disease and the mechanisms by which STEP activity is increased in this illness. Both genetic lowering of STEP levels and pharmacological inhibition of STEP activity in mouse models of Alzheimer's disease reverse the biochemical and cognitive abnormalities that are present. These findings suggest that STEP is an important point for modulation of proteins required for synaptic plasticity.

Profiling changes in cortical astroglial cells following chronic stress

“…This may also explain the lower general transcriptional throughput highlighted by the GSEA analysis. The top downregulated genes include Synpo2 and EGR3, which are necessary for synaptic plasticity, long-term potentiation (LTP), learning and memory [ 47 , 48 ]; Ptpn7, which belongs to a family of protein tyrosine phosphatases also necessary for synaptic plasticity and associated with models of developmental delay [ 49 ]; and Gprin3, part of the NMDA receptor complex which regulates the synaptic protein PSD-95 [ 50 ] (Fig. 3c, d , Supplemental Data File DEG and Supplemental Fig.…”

The activity of the Striatal‐enriched protein tyrosine phosphatase in neuronal cells is modulated by adenosine A2A receptor

“…Several studies demonstrated the involvement of STEP in the mechanism of learning and memory. In fact, STEP down‐regulates membrane expression of NMDARs and AMPARs (Braithwaite et al ; Zhang et al ), thus opposing the development of synaptic strengthening and modulating synaptic plasticity (Pelkey et al ; Jang et al ; Kamceva et al ). In addition, STEP levels are elevated in postmortem samples of AD patients (Zhang et al ), in animal models of AD, and in the brain of individuals with mild cognitive impairment (Xu et al ; Castonguay et al ).…”

“…High levels of STEP are present in human post‐mortem samples and animal models of Alzheimer's disease (AD), Parkinson's disease (PD) and schizophrenia, and in animal models of fragile X syndrome (Goebel‐Goody et al ). Low levels of STEP activity are instead observed in another group of disorders that include ischemia, Huntington's disease (HD), alcohol abuse, and stress disorders (Karasawa and Lombroso ; Kamceva et al ). Recent studies indicated that pharmacogenetic modulation of STEP improves cognitive deficits in mouse models of AD (Zhang et al ; Xu et al ), behavioral and synaptic abnormalities in a rodent model of fragile X syndrome (Chatterjee et al ), motor and cognitive functions in a mouse model of HD (Garcia‐Forn et al ), and symptoms in mouse models of schizophrenia (Xu et al ), suggesting that STEP can be considered a therapeutic target against these neuropsychiatric diseases.…”

Corticotropin-Releasing Hormone Signaling in the Oval Bed Nucleus of the Stria Terminalis Mediates Chronic Stress-Induced Negative Valence Behaviors Associated with Anxiety

“…We also investigated the effects of CVMS on STEP (also known as protein tyrosine phosphatase nonreceptor type 5, PTPN5). STEP is a brain-specific tyrosine phosphatase that dephosphorylates and inactivates several kinases (including ERK1/2 and p38MAPK, Fyn) (96) and STEP overexpression enhances stress resilience (97). Furthermore, STEP loss-of-function increases susceptibility to stress-induced cognitive deficits (98).…”