Roles of p75NTR, Long-Term Depression, and Cholinergic Transmission in Anxiety and Acute Stress Coping
Open accessAbstract
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.
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Pro-BDNF binding to p75NTR promotes long-term depression.
“Pro-BDNF binding to p75NTR has also been shown to induce pruning of axons and dendrites85,88–91 and promote long-term depression (LTD)92–94.”
From Neuronal plasticity and neurotrophic factors in drug responses (2017) · cites this paper as [93]
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- Authors
- Martinowich, K., Schloesser, R. J., Lu, Y., Jimenez, D. V., Paredes, D., Greene, J. S., Greig, N. H., Manji, H. K., & Lu, B.
- Affiliations
- National Institutes of Health (US)
- National Institute of Neurological Disorders and Stroke (US)
- National Institute on Aging (US)
- Corresponding author
- Lu, Bai
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 71
- Issue
- 1
- Pages
- 75-83
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC3230751
- OpenAlex
- W1998627088
- Cited by
- 48
- References
- 49
- Citations by year
- 2026: 3 · 2024: 2 · 2023: 3 · 2022: 7 · 2021: 4 · 2020: 1 · 2019: 3 · 2018: 2 · 2017: 4 · 2016: 6 · 2015: 3 · 2014: 4 · 2013: 4 · 2012: 2
- FWCI
- 1.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (ZIAMH002910)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- p75 neurotrophin receptor, long-term depression, cholinergic neurotransmission, anxiety, hippocampus, basal forebrain cholinergic neurons, stress recovery, synaptic plasticity, stress behavior
- MeSH terms
- Acetylcholine, Adaptation, Psychological, Analysis of Variance, Animals, Anxiety, Biophysics, Disease Models, Animal, Dose-Response Relationship, Drug, Electric Stimulation, Exploratory Behavior, Hippocampus, Male, Mice, Inbred C57BL, Microinjections, Stress, Psychological, Time Factors, N-Methylaspartate, Proto-Oncogene Proteins c-fos, Receptors, Nerve Growth Factor, Microdialysis, Mice, Knockout, Patch-Clamp Techniques, Cholinergic Agents, Maze Learning, Long-Term Synaptic Depression, Mice, In Vitro Techniques
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