Presynaptic PTPσ regulates postsynaptic NMDA receptor function through direct adhesion-independent mechanisms

• Published in: eLife 2020-03, Vol.9
• Main Authors: Kim, Kyungdeok, Shin, Wangyong, Kang, Muwon, Lee, Suho, Kim, Doyoun, Kang, Ryeonghwa, Jung, Yewon, Cho, Yisul, Yang, Esther, Kim, Hyun, Bae, Yong Chul, Kim, Eunjoon
• Format: Article
• Language: English
• Subjects: Adhesion; Animals; Gene Expression Regulation - physiology; Glutamic acid receptors (ionotropic); Kinases; long-term potentiation; Mice; Mice, Transgenic; Morphology; Mutants; N-Methyl-D-aspartic acid receptors; Neuroimaging; Neurons; Neuroscience; nmda receptors; novelty recognition; Open Field Test; Phosphatase; Phosphotyrosine; Protein interaction; Protein-tyrosine-phosphatase; Proteins; Receptor-Like Protein Tyrosine Phosphatases, Class 2 - genetics; Receptor-Like Protein Tyrosine Phosphatases, Class 2 - metabolism; Receptors, N-Methyl-D-Aspartate - genetics; Receptors, N-Methyl-D-Aspartate - metabolism; Reinforcement; Rodents; Social interactions; Synapses; Synapses - physiology; synaptic adhesion; Synaptic plasticity; Synaptic Transmission - physiology; tyrosine phosphatase
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.54224

Synaptic adhesion molecules regulate synapse development and function. However, whether and how presynaptic adhesion molecules regulate postsynaptic NMDAR function remains largely unclear. Presynaptic LAR family receptor tyrosine phosphatases (LAR-RPTPs) regulate synapse development through mechanisms that include trans-synaptic adhesion; however, whether they regulate postsynaptic receptor functions remains unknown. Here we report that presynaptic PTPσ, a LAR-RPTP, enhances postsynaptic NMDA receptor (NMDAR) currents and NMDAR-dependent synaptic plasticity in the hippocampus. This regulation does not involve trans-synaptic adhesions of PTPσ, suggesting that the cytoplasmic domains of PTPσ, known to have tyrosine phosphatase activity and mediate protein-protein interactions, are important. In line with this, phosphotyrosine levels of presynaptic proteins, including neurexin-1, are strongly increased in PTPσ-mutant mice. Behaviorally, PTPσ-dependent NMDAR regulation is important for social and reward-related novelty recognition. These results suggest that presynaptic PTPσ regulates postsynaptic NMDAR function through trans-synaptic and direct adhesion-independent mechanisms and novelty recognition in social and reward contexts.