The tyrosine phosphatase STEP constrains amygdala-dependent memory formation and neuroplasticity

Abstract

STriatal-Enriched protein tyrosine Phosphatase (STEP; PTPN5) is expressed in brain regions displaying adult neuroplasticity. STEP modulates neurotransmission by dephosphorylating regulatory tyrosine residues on its substrates. In this way, STEP inactivates extracellular-signal-regulated kinase 1/2 (ERK1/2), limiting the duration and spatial distribution of ERK signaling. Two additional substrates, the tyrosine kinase Fyn and the NR2B subunit of the N-methyl-d-aspartic acid receptor, link STEP to glutamate receptor internalization in the synapse. Thus, STEP may act through parallel pathways to oppose the development of experience-dependent synaptic plasticity. We examined the hypothesis that the absence of STEP facilitates amygdala-dependent behavioral and synaptic plasticity (i.e., fear conditioning and long-term potentiation) using STEP-deficient mice (STEP KO). These mice show no detectable expression of STEP in the brain along with increases in Tyr phosphorylation of STEP substrates. Here we demonstrate that STEP KO mice also display augmented fear conditioning as measured by an enhancement in conditioned suppression of instrumental response when a fear-associated conditioned stimulus was presented. Deletion of STEP also increases long-term potentiation and ERK phosphorylation in the lateral amygdala. The current experiments demonstrate that deletion of STEP can enhance experience-induced neuroplasticity and memory formation and identifies STEP as a target for pharmacological treatment aimed at improving the formation of long-term memories.

Fig. 1

Deletion of STEP levels increases amygdala-dependent fear learning. Deletion of STEP levels increases amygdala-dependent fear learning. Animals hetero- or homozygous for the deletion of the STEP gene displayed greater conditioned suppression when presented with an auditory CS+ that had previously been associated with foot shock. Data shown is the average suppression ratio over the five CS+ presentations. ANOVA analysis identified a main effect of genotype (p ≤ 0.05) on conditioned suppression.

Fig. 2

Increased amygdala ERK1/2 activity in STEP−/− mice. (A) Tissue punches from the LA and the CeN were analyzed by SDS–polyacrylamide gel electrophoresis and Western blots probed with anti-ERK1/2, anti-pERK1/2 and anti-STEP antibodies to determine the level of ERK1/2 activity and distribution of STEP isoforms in these regions. (B) Histograms showing an increase in pERK in both the LA and the CeN of STEP−/− mice (*p ≤ 0.05 and **p ≤ 0.01).

Fig. 3

Deletion of STEP facilitates induction of LTP in LA without affecting basal synaptic transmission. (A) Basal synaptic transmission and LTP in STEP−/− mice. Synaptic responses to increasing stimulus intensity (upper left panel). The fEPSP amplitude is plotted as a function of stimulus intensity in slices from WT mice (n = 9 slices, 3 mice, black circles) or from STEP−/− (KO) mice (n = 11 slices, 3 mice, open circles). (B) Paired synaptic responses from WT and STEP−/− slices at different interstimulus intervals do not differ (upper right panel). Ratio of the second fEPSP the first fEPSP (mean ± SEM) is plotted for WT (n = 9 slices, 3 mice, black circles) and STEP−/− mice (n = 11 slices, 3 mice, open circles). (C) Pooled fEPSP amplitude (lower panel) (mean ± SEM) is plotted for WT slices (n = 9 slices, 3 mice, black circles) and STEP−/− slices (n = 10 slices, 3 mice, open circles circles). Tetanic stimulation was delivered at t = 20 min as indicated by the arrow.