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

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.