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.
Key Words
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Article info
Publication history
Published online: November 03, 2006
Accepted:
August 2,
2006
Received in revised form:
August 1,
2006
Received:
June 5,
2006
Identification
Copyright
© 2007 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
