Roles of p75 NTR, long-term depression, and cholinergic transmission in anxiety and acute stress coping

Keri Martinowich, Robert J. Schloesser, Yuan Lu, Dennisse V. Jimenez, Daniel Paredes, Joshua S. Greene, Nigel H. Greig, Husseini K. Manji, Bai Lu

Research output: Contribution to journalArticle

Abstract

Background: Stress is causally associated with anxiety. Although the underlying cellular mechanisms are not well understood, the basal forebrain cholinergic neurons have been implicated in stress response. p75 NTR is a panneurotrophin receptor expressed almost exclusively in basal forebrain cholinergic neurons in adult brain. This study investigated whether and how p75 NTR, via regulation of the cholinergic system and hippocampal synaptic plasticity, influences stress-related behaviors. Methods: We used a combination of slice electrophysiology, behavioral analyses, pharmacology, in vivo microdialysis, and neuronal activity mapping to assess the role of p75 NTR in mood and stress-related behaviors and its underlying cellular and molecular mechanisms. Results: We show that acute stress enables hippocampal long-term depression (LTD) in adult wild-type mice but not in mice lacking p75 NTR. The p75 NTR mutant mice also exhibit two distinct behavioral impairments: baseline anxiety-like behavior and a deficit in coping with and recovering from stressful situations. Blockade of stress-enabled LTD with a GluA2-derived peptide impaired stress recovery without affecting baseline anxiety. Pharmacological manipulations of cholinergic transmission mimicked the p75 NTR perturbation in both baseline anxiety and responses to acute stress. Finally, we show evidence of misregulated cholinergic signaling in animals with p75 NTR deletion. Conclusions: Our results suggest that loss of p75 NTR leads to changes in hippocampal cholinergic signaling, which may be involved in regulation of stress-enabled hippocampal LTD and in modulating behaviors related to stress and anxiety.

Original languageEnglish (US)
Pages (from-to)75-83
Number of pages9
JournalBiological psychiatry
Volume71
Issue number1
DOIs
StatePublished - Jan 1 2012
Externally publishedYes

Keywords

  • Anxiety
  • basal forebrain
  • hippocampus
  • long-term depression
  • neurotrophin
  • p75

ASJC Scopus subject areas

  • Biological Psychiatry

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    Martinowich, K., Schloesser, R. J., Lu, Y., Jimenez, D. V., Paredes, D., Greene, J. S., Greig, N. H., Manji, H. K., & Lu, B. (2012). Roles of p75 NTR, long-term depression, and cholinergic transmission in anxiety and acute stress coping. Biological psychiatry, 71(1), 75-83. https://doi.org/10.1016/j.biopsych.2011.08.014