The striatal-enriched protein tyrosine phosphatase gates long-term potentiation and fear memory in the lateral amygdala.
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.
Paul
Surojit
S
Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Olausson
Peter
P
Venkitaramani
Deepa V
DV
Ruchkina
Irina
I
Moran
Timothy D
TD
Tronson
Natalie
N
Mills
Evan
E
Hakim
Shawn
S
Salter
Michael W
MW
Taylor
Jane R
JR
Lombroso
Paul J
PJ
D000161:Acoustic Stimulation; D000607:Aminoacetonitrile / Q000031:analogs & derivatives / Q000494:pharmacology; D000679:Amygdala / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002478:Cells, Cultured; D003214:Conditioning, Classical / Q000502:physiology; D003513:Cycloheximide / Q000494:pharmacology; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005239:Fear / Q000502:physiology*; D005260:Female; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000502:physiology*; D008568:Memory / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017072:Neostriatum / Q000378:metabolism / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017354:Point Mutation / Q000235:genetics / Q000502:physiology; D011247:Pregnancy; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014178:Translocation, Genetic / Q000502:physiology
D004791:Enzyme Inhibitors; D011500:Protein Synthesis Inhibitors; C424127:SL 327; D000607:Aminoacetonitrile; D003513:Cycloheximide; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D017027:Protein Tyrosine Phosphatases