Targeting the postsynaptic scaffolding protein PSD-95 enhances BDNF signaling to mitigate depression-like behaviors in mice

Author:

Shi Xin1ORCID,Zhou Xiao-zhong12ORCID,Chen Gang3ORCID,Luo Wei-feng1ORCID,Zhou Chengyu4ORCID,He Tian-ju1,Naik Mandar T.5ORCID,Jiang Qin6ORCID,Marshall John5ORCID,Cao Cong1ORCID

Affiliation:

1. Clinical Research Center of Neurological Disease, Second Affiliated Hospital of Soochow University, Institution of Neuroscience, Soochow University, Suzhou 215123, China.

2. Department of Orthopedics, Second Affiliated Hospital of Soochow University, Suzhou 215004, Jiangsu, China.

3. Department of Neurosurgery, First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China.

4. Department of Neuroscience, Case Western Reserve University, Cleveland, OH 44106, USA.

5. Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, RI 02912, USA.

6. Affiliated Eye Hospital, Nanjing Medical University, Nanjing 210029, China.

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–Gα i1/3 –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 Gα i1/3 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.

Publisher

American Association for the Advancement of Science (AAAS)

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