Neurotrophin-3 Enhances the Synaptic Organizing Function of TrkC-Protein Tyrosine Phosphatase σ in Rat Hippocampal Neurons.
Neurotrophin-3 (NT-3) and its high-affinity receptor TrkC play crucial trophic roles in neuronal differentiation, axon outgrowth, and synapse development and plasticity in the nervous system. We demonstrated previously that postsynaptic TrkC functions as a glutamatergic synapse-inducing (synaptogenic) cell adhesion molecule trans-interacting with presynaptic protein tyrosine phosphatase σ (PTPσ). Given that NT-3 and PTPσ bind distinct domains of the TrkC extracellular region, here we tested the hypothesis that NT-3 modulates TrkC/PTPσ binding and synaptogenic activity. NT-3 enhanced PTPσ binding to cell surface-expressed TrkC and facilitated the presynapse-inducing activity of TrkC in rat hippocampal neurons. Imaging of recycling presynaptic vesicles combined with TrkC knockdown and rescue approaches demonstrated that NT-3 rapidly potentiates presynaptic function via binding endogenous postsynaptic TrkC in a tyrosine kinase-independent manner. Thus, NT-3 positively modulates the TrkC-PTPσ complex for glutamatergic presynaptic assembly and function independently from TrkC kinase activation. Our findings provide new insight into synaptic roles of neurotrophin signaling and mechanisms controlling synaptic organizing complexes. Significance statement: Although many synaptogenic adhesion complexes have been identified in recent years, little is known about modulatory mechanisms. Here, we demonstrate a novel role of neurotrophin-3 in synaptic assembly and function as a positive modulator of the TrkC-protein tyrosine phosphatase σ complex. This study provides new insight into the involvement of neurotrophin signaling in synapse development and plasticity, presenting a molecular mechanism that may underlie previous observations of short- and long-term enhancement of presynaptic function by neurotrophin. Given the links of synaptogenic adhesion molecules to autism and schizophrenia, this study might also contribute to a better understanding of the pathogenesis of these disorders and provide a new direction for ameliorating imbalances in synaptic signaling networks.
Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.
Ina
I
Ammendrup-Johnsen
Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada.
Yusuke
Y
Naito
Brain Research Centre and Department of Psychiatry, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada, hideto.takahashi@ircm.qc.ca acraig@mail.ubc.ca.
Ann Marie
AM
Craig
Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada, Department of Medicine, Université de Montréal, Montreal, Quebec H3T 1J4, Canada, and Division of Experimental Medicine, McGill University, Montreal, Quebec H3A 0G4, Canada hideto.takahashi@ircm.qc.ca acraig@mail.ubc.ca.
Hideto
http://orcid.org/0000-0002-6473-5060
H
Takahashi
D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D020933:Neurotrophin 3 / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D020812:Receptor, trkC / Q000235:genetics / Q000378:metabolism*; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism* / Q000502:physiology
D020933:Neurotrophin 3; D020812:Receptor, trkC; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2
PTPσ; TrkC; neurotrophin-3; synapse organization; synaptic plasticity