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Author Notes:

E-mail Address : drainni@emory.edu

We would like to thank laboratory members for helpful discussions and critical reading of the manuscript.

Especially, we would like to thank David E. Ehrlich and Steven J. Ryan for helping with rat brains dissection.

Conflict of interest statement : All authors report no biomedical financial interests or potential conflicts of interest.


Research Funding:

This work was supported by MH-072908 to DGR, and MH-01527 to PJL from the National Institute of Mental Health (NIMH), and by the National Center for Research Resources P51RR169, which is supported by the Office of Research Infrastructure Programs/OD P51OD11107. JD is supported by NIMH K99MH-096746 grant.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Psychiatry
  • Neurosciences & Neurology
  • Anxiety
  • bed nucleus of the stria terminalis
  • BNST
  • chronic stress
  • corticotrophin releasing factor
  • CRF
  • STEP
  • striatal-enriched protein tyrosine phosphatase
  • FEAR

Striatal-enriched protein tyrosine phosphatase - STEPs toward understanding chronic stress-induced activation of CRF neurons in the rat BNST


Journal Title:

Biological Psychiatry


Volume 74, Number 11


, Pages 817-826

Type of Work:

Article | Post-print: After Peer Review


Background Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific protein tyrosine phosphatase that opposes the development of synaptic strengthening and the consolidation of fear memories. In contrast, stress facilitates fear memory formation, potentially by activating corticotrophin releasing factor (CRF) neurons in the anterolateral cell group of the bed nucleus of the stria terminalis (BNSTALG). Methods Here, using dual-immunofluorescence, single-cell reverse transcriptase polymerase chain reaction, quantitative reverse transcriptase polymerase chain reaction, Western blot, and whole-cell patch-clamp electrophysiology, we examined the expression and role of STEP in regulating synaptic plasticity in rat BNST ALG neurons and its modulation by stress. Results Striatal-enriched protein tyrosine phosphatase was selectively expressed in CRF neurons in the oval nucleus of the BNSTALG. Following repeated restraint stress (RRS), animals displayed a significant increase in anxiety-like behavior, which was associated with a downregulation of STEP messenger RNA and protein expression in the BNSTALG, as well as selectively enhancing the magnitude of long-term potentiation (LTP) induced in Type III, putative CRF neurons. To determine if the changes in STEP expression following RRS were mechanistically related to LTP facilitation, we examined the effects of intracellular application of STEP on the induction of LTP. STEP completely blocked the RRS-induced facilitation of LTP in BNSTALG neurons. Conclusions Hence, STEP acts to buffer CRF neurons against excessive activation, while downregulation of STEP after chronic stress may result in pathologic activation of CRF neurons in the BNSTALG and contribute to prolonged states of anxiety. Thus, targeted manipulations of STEP activity might represent a novel treatment strategy for stress-induced anxiety disorders. © 2013 Society of Biological Psychiatry.

Copyright information:

© 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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