Elsevier

Biological Psychiatry

Volume 61, Issue 9, 1 May 2007, Pages 1049-1061
Biological Psychiatry

Original article
The Striatal-Enriched Protein Tyrosine Phosphatase Gates Long-Term Potentiation and Fear Memory in the Lateral Amygdala

https://doi.org/10.1016/j.biopsych.2006.08.005Get rights and content

Background

Formation of long-term memories is critically dependent on extracellular-regulated kinase (ERK) signaling. Activation of the ERK pathway by the sequential recruitment of mitogen-activated protein kinases is well understood. In contrast, the proteins that inactivate this pathway are not as well characterized.

Methods

Here we tested the hypothesis that the brain-specific striatal-enriched protein tyrosine phosphatase (STEP) plays a key role in neuroplasticity and fear memory formation by its ability to regulate ERK1/2 activation.

Results

STEP co-localizes with the ERKs within neurons of the lateral amygdala. A substrate-trapping STEP protein binds to the ERKs and prevents their nuclear translocation after glutamate stimulation in primary cell cultures. Administration of TAT-STEP into the lateral amygdala (LA) disrupts long-term potentiation (LTP) and selectively disrupts fear memory consolidation. Fear conditioning induces a biphasic activation of ERK1/2 in the LA with an initial activation within 5 minutes of training, a return to baseline levels by 15 minutes, and an increase again at 1 hour. In addition, fear conditioning results in the de novo translation of STEP. Inhibitors of ERK1/2 activation or of protein translation block the synthesis of STEP within the LA after fear conditioning.

Conclusions

Together, these data imply a role for STEP in experience-dependent plasticity and suggest that STEP modulates the activation of ERK1/2 during amygdala-dependent memory formation. The regulation of emotional memory by modulating STEP activity may represent a target for the treatment of psychiatric disorders such as posttraumatic stress disorder (PTSD), panic, and anxiety disorders.

Section snippets

Reagents

Cycloheximide, SL327, and glutamate were from Calbiochem (La Jolla, California). The anti-ERK2 polyclonal antibody that only recognizes ERK2 (C-14) and the anti-myc monoclonal antibody (sc-40) were purchased from Santa Cruz Biotechnology (Santa Cruz, California). Anti-p44/42 ERK antibodies that detect ERK1/2 when dually phosphorylated at Thr-202 and Tyr-204 (TPEYP) were obtained from Cell Signaling Technology (Beverly, Massachusetts). Bicuculline was obtained from Tocris Cookson (Ballwin,

STEP is Present in the Amygdala and Co-localizes with ERK2

We first investigated whether STEP is co-expressed with ERK2 in the LA neurons relevant to fear conditioning by using immunofluorescent staining of rat brain coronal sections. For these experiments, we used an antibody specific to ERK2. Striatal-enriched tyrosine phosphatase and ERK2 co-localized in most cells of the dorsolateral and ventrolateral amygdala (LAd and LAv) (Figure 1A). To determine which STEP isoforms were expressed in LA neurons, we performed Western blot analyses on tissue

Discussion

Here we report the ability of the PTP STEP to interfere with memory consolidation in a Pavlovian fear conditioning paradigm and it does so, in part, through its ability to regulate the ERK signaling pathway. In the lateral amygdala, activation of the ERK pathway results in long-term changes in synaptic activity that are thought to underlie the consolidation of a Pavlovian auditory fear memory (Rodrigues et al 2004, Schafe et al 2000, Schafe and LeDoux 2000). Activated ERK1/2 is required for the

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