The TrkC-PTPσ complex governs synapse maturation and anxiogenic avoidance via synaptic protein phosphorylation
The precise organization of pre- and postsynaptic terminals is crucial for normal synaptic function in the brain. In addition to its canonical role as a neurotrophin-3 receptor tyrosine kinase, postsynaptic TrkC promotes excitatory synapse organization through interaction with presynaptic receptor-type tyrosine phosphatase PTPσ. To isolate the synaptic organizer function of TrkC from its role as a neurotrophin-3 receptor, we generated mice carrying TrkC point mutations that selectively abolish PTPσ binding. The excitatory synapses in mutant mice had abnormal synaptic vesicle clustering and postsynaptic density elongation, more silent synapses, and fewer active synapses, which additionally exhibited enhanced basal transmission with impaired release probability. Alongside these phenotypes, we observed aberrant synaptic protein phosphorylation, but no differences in the neurotrophin signaling pathway. Consistent with reports linking these aberrantly phosphorylated proteins to neuropsychiatric disorders, mutant TrkC knock-in mice displayed impaired social responses and increased avoidance behavior. Thus, through its regulation of synaptic protein phosphorylation, the TrkC-PTPσ complex is crucial for the maturation, but not formation, of excitatory synapses in vivo.
Authors
- Artur Kania (ORCID: https://orcid.org/0000-0002-5209-2520)
- Nayoung Yi
- Nicolas Chofflet (ORCID: https://orcid.org/0009-0002-9175-1653)
- Hidetaka Kosako (ORCID: https://orcid.org/0000-0003-3228-6368)
- Alfred Kihoon Lee
- Benjamin Feller (ORCID: https://orcid.org/0009-0007-3703-8036)
- Husam Khaled (ORCID: https://orcid.org/0009-0000-7205-4380)
- Yusuke Naito
- Hideto Takahashi (ORCID: https://orcid.org/0000-0002-6473-5060)
- Steven A. Connor (ORCID: https://orcid.org/0000-0002-0198-5134)
- Farin B. Bourojeni (ORCID: https://orcid.org/0000-0002-0967-770X)
- Mai Inagaki (ORCID: https://orcid.org/0000-0001-8664-6424)
- Kyle Patel
- Zahra Ghasemi (ORCID: https://orcid.org/0000-0003-0212-3525)
- Masanori Tachikawa (ORCID: https://orcid.org/0000-0001-5711-5691)
Institutions
- York University (CA)
- Montreal Clinical Research Institute (CA)
- McGill University (CA)
- Université de Montréal (CA)
- Tokushima University (JP)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2024-09-27
- DOI
- https://doi.org/10.1038/s44318-024-00252-9
- Citations
- 2
- Primary Topic
- Cellular transport and secretion
- Type
- article
- Field-Weighted Citation Impact
- 0.65
Funders
- McGill University
- Alzheimer Society
- Ministry of Education, Culture, Sports, Science and Technology
- Canada Research Chairs
- Institut de Recherche Clinique De Montréal
- University of Tokushima
- National Institutes of Health
- Alzheimer Society Research Program
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada
- Fonds de Recherche du Québec - Santé
- Japan Society for the Promotion of Science
- National Institute of Mental Health
- Institute of Neurosciences, Mental Health and Addiction