1. The TrkC-PTPσ complex governs synapse maturation and anxiogenic avoidance via synaptic protein phosphorylation.
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Khaled, Husam, Ghasemi, Zahra, Inagaki, Mai, Patel, Kyle, Naito, Yusuke, Feller, Benjamin, Yi, Nayoung, Bourojeni, Farin B, Lee, Alfred Kihoon, Chofflet, Nicolas, Kania, Artur, Kosako, Hidetaka, Tachikawa, Masanori, Connor, Steven, and Takahashi, Hideto
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SYNAPTIC vesicles , *NEURAL transmission , *NEUROTROPHIN receptors , *PROTEIN-tyrosine kinases , *NEUROBEHAVIORAL disorders - Abstract
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. Synopsis: Interaction between neurotrophin-3 (NT-3) receptor TrkC and phosphatase PTPσ creates an excitatory synaptic organizing complex. Analysis of a new knock-in (KI) mouse model with disrupted TrkC binding to PTPσ, but not to NT-3, reveals the in vivo roles of the TrkC-PTPσ complex in synapse maturation and brain function. Selective loss of TrkC-PTPσ interaction in mice causes abnormal synaptic vesicle clustering and elongation of the postsynaptic density in excitatory synapses. Disruption of TrkC-PTPσ interaction results in mice with more silent and fewer active synapses, the latter displaying enhanced basal synaptic transmission and impaired release probability. The TrkC-PTPσ complex targets a specific set of synaptic proteins for phosphorylation, independent of canonical neurotrophin signaling pathways. TrkC KI mice display specific behavioral abnormalities, including social abnormalities and increased avoidance behavior in unfamiliar anxiogenic conditions. Inhibiting the interaction between postsynaptic TrkC and presynaptic PTPσ results in abnormal excitatory synapse maturation and anxiety-like behaviors in mice. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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