Striatal‐enriched protein tyrosine phosphatase (STEP) knockout mice have enhanced hippocampal memory

Abstract

STEP is a brain-specific phosphatase that opposes synaptic strengthening by the regulation of key synaptic signaling proteins. Previous studies suggest a possible role for STriatal-Enriched protein tyrosine Phosphatase (STEP) in learning and memory. To demonstrate the functional importance of STEP in learning and memory, we generated STEP knockout (KO) mice and examined the effect of deletion of STEP on behavioral performance, as well as the phosphorylation and expression of its substrates. Here we report that loss of STEP leads to significantly enhanced performance in hippocampal-dependent learning and memory tasks. In addition, STEP KO mice displayed greater dominance behavior, although they were normal in their motivation, motor coordination, visual acuity and social interactions. STEP KO mice displayed enhanced tyrosine phosphorylation of extracellular-signal regulated kinase 1/2 (ERK1/2), the NR2B subunit of the N-methyl-D-aspartate receptor (NMDAR), Proline-rich tyrosine kinase (Pyk2), as well as an increased phosphorylation of ERK1/2 substrates. Concomitant to the increased phosphorylation of NR2B, synaptosomal expression of NR1/NR2B NMDARs was increased in STEP KO mice, as was the GluR1/GluR2 containing α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPAR), providing a potential molecular mechanism for the improved cognitive performance. The data support a role for STEP in the regulation of synaptic strengthening. The absence of STEP improves cognitive performance, and may do so by the regulation of downstream effectors necessary for synaptic transmission.

Therapeutic Implications for Striatal-Enriched Protein Tyrosine Phosphatase (STEP) in Neuropsychiatric Disorders

“…ERK1/2 phosphorylation is significantly elevated in the striatum, hippocampus, and central/lateral amygdala of STEP KO mice compared with WT littermates (Venkitaramani et al, , 2011, providing additional support for the regulation of ERK1/2 by STEP. DHPG normally enhances phosphorylation and activation of ERK1/2 (Kim et al, 2008a), and this is more pronounced in STEP KOs relative to WT, suggesting that STEP limits the activation of ERK1/2 after mGluR stimulation ).…”

“…DHPG normally enhances phosphorylation and activation of ERK1/2 (Kim et al, 2008a), and this is more pronounced in STEP KOs relative to WT, suggesting that STEP limits the activation of ERK1/2 after mGluR stimulation ). Downstream of ERK1/2 activation, the transcription factors CREB and Elk1 are also hyperphosphorylated in STEP KOs compared with WT mice (Venkitaramani et al, 2011). Thus, alterations in STEP levels and/or activity can have a lasting impact on gene transcription via its regulation of ERK1/2.…”

“…4) (Snyder et al, 2005;Braithwaite et al, 2006;Zhang et al, 2008;Zhang et al, 2010;Venkitaramani et al, 2011). In the case of NMDARs, STEP modulates the phosphorylation of the GluN2B subunit by two parallel pathways: by direct dephosphorylation of GluN2B Tyr 1472 (Snyder et al, 2005;Kurup et al, 2010) and indirectly via dephosphorylation and inactivation of the SFK Fyn (Fig.…”

Neural functions of calcineurin in synaptic plasticity and memory: Figure 1.

“…Conversely, overexpression of CaN or STEP impairs long-lasting LTP (Mansuy et al 1998b;Winder et al 1998;Pelkey et al 2002;Paul et al 2007). On a behavioral level, CaN or STEP inhibition improves memory (Malleret et al 2001;Venkitaramani et al 2011), while their overexpression disrupts learning and memory consolidation (Mansuy et al 1998a,b;Paul et al 2007). Interestingly, both STEP and CaN have been implicated in the molecular pathways of Ab toxicity in Alzheimer's disease (Abdul et al 2009;Kurup et al 2010).…”

PSD-95 stabilizes NMDA receptors by inducing the degradation of STEP 61

“…Importantly, GluN2B Y1472 phosphorylation promotes surface expression of GluN2B-containing NMDARs by disrupting binding to the AP-2 clathrin-associated adaptor protein complex, which targets proteins for endocytosis (30)(31)(32). In contrast, STEP 61 dephosphorylates GluN2B Y1472, leading to internalization of NMDAR complexes (17,33,34). STEP 61 also dephosphorylates Fyn at a regulatory tyrosine residue (Y420), thereby inhibiting its activity (35) and indirectly decreasing Y1472 phosphorylation.…”