The TrkC-PTPσ complex governs synapse maturation and anxiogenic avoidance via synaptic protein phosphorylation.

IF 9.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY EMBO Journal Pub Date : 2024-09-27 DOI:10.1038/s44318-024-00252-9
Husam Khaled, Zahra Ghasemi, Mai Inagaki, Kyle Patel, Yusuke Naito, Benjamin Feller, Nayoung Yi, Farin B Bourojeni, Alfred Kihoon Lee, Nicolas Chofflet, Artur Kania, Hidetaka Kosako, Masanori Tachikawa, Steven Connor, Hideto Takahashi
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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.

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TrkC-PTPσ复合体通过突触蛋白磷酸化调节突触成熟和焦虑性回避。
突触前和突触后终端的精确组织对大脑突触功能的正常发挥至关重要。除了作为神经营养素-3受体酪氨酸激酶的典型作用外,突触后TrkC还通过与突触前受体型酪氨酸磷酸酶PTPσ的相互作用促进兴奋性突触的组织。为了将TrkC的突触组织功能与其作为神经营养素-3受体的作用分离开来,我们培育了携带TrkC点突变的小鼠,这种突变选择性地取消了PTPσ的结合。突变小鼠的兴奋性突触具有异常的突触小泡聚集和突触后密度伸长、更多的沉默突触和更少的活跃突触,此外,这些突触还表现出基础传递增强,释放概率受损。除了这些表型,我们还观察到突触蛋白磷酸化异常,但神经营养素信号通路没有差异。与这些异常磷酸化蛋白与神经精神疾病有关的报道一致,突变的TrkC基因敲入小鼠显示出社交反应受损和回避行为增加。因此,通过调节突触蛋白磷酸化,TrkC-PTPσ复合物对兴奋性突触在体内的成熟(而非形成)至关重要。
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来源期刊
EMBO Journal
EMBO Journal 生物-生化与分子生物学
CiteScore
18.90
自引率
0.90%
发文量
246
审稿时长
1.5 months
期刊介绍: The EMBO Journal has stood as EMBO's flagship publication since its inception in 1982. Renowned for its international reputation in quality and originality, the journal spans all facets of molecular biology. It serves as a platform for papers elucidating original research of broad general interest in molecular and cell biology, with a distinct focus on molecular mechanisms and physiological relevance. With a commitment to promoting articles reporting novel findings of broad biological significance, The EMBO Journal stands as a key contributor to advancing the field of molecular biology.
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