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- Title
Targeting the postsynaptic scaffolding protein PSD-95 enhances BDNF signaling to mitigate depression-like behaviors in mice.
- Authors
Shi, Xin; Zhou, Xiao-zhong; Chen, Gang; Luo, Wei-feng; Zhou, Chengyu; He, Tian-ju; Naik, Mandar T.; Jiang, Qin; Marshall, John; Cao, Cong
- Abstract
Signaling mediated by brain-derived neurotrophic factor (BDNF), which is supported by the postsynaptic scaffolding protein PSD-95, has antidepressant effects. Conversely, clinical depression is associated with reduced BDNF signaling. We found that peptidomimetic compounds that bind to PSD-95 promoted signaling by the BDNF receptor TrkB in the hippocampus and reduced depression-like behaviors in mice. The compounds CN2097 and Syn3 both bind to the PDZ3 domain of PSD-95, and Syn3 also binds to an α-helical region of the protein. Syn3 reduced depression-like behaviors in two mouse models of stress-induced depression; CN2097 had similar but less potent effects. In hippocampal neurons, application of Syn3 enhanced the formation of TrkB–Gαi1/3–PSD-95 complexes and potentiated downstream PI3K-Akt-mTOR signaling. In mice subjected to chronic mild stress (CMS), systemic administration of Syn3 reversed the CMS-induced, depression-associated changes in PI3K-Akt-mTOR signaling, dendrite complexity, spine density, and autophagy in the hippocampus and reduced depression-like behaviors. Knocking out Gαi1/3 in hippocampal neurons prevented the therapeutic effects of Syn3, indicating dependence of these effects on the TrkB pathway. The findings suggest that compounds that induce the formation of PSD-95–TrkB complexes have therapeutic potential to alleviate depression. Editor's summary: The neurotrophic factor BDNF and its receptor TrkB have antidepressant effects. Because direct modulators of this ligand-receptor pair have limited therapeutic potential, Shi et al. instead tested the effects of peptides designed to structurally support BDNF-TrkB signaling intracellularly. Syn3 and CN2097, which bind to the postsynaptic scaffolding protein PSD-95, increased TrkB complex formation and BDNF-induced pathway activation in hippocampal neurons. Syn3 and, to a lesser extent, CN2097 reversed the neuronal and depression-like behavioral effects of chronic stress in mice, showing that targeting PSD-95 has antidepressant potential. —Leslie K. Ferrarelli
- Subjects
SCAFFOLD proteins; BRAIN-derived neurotrophic factor; DENDRITES; MICE; PSYCHOLOGICAL stress; SEROTONIN receptors
- Publication
Science Signaling, 2024, Vol 17, Issue 834, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.adn4556