Specification of neural circuit architecture shaped by context-dependent patterned LAR-RPTP microexons

• Published in: Nature communications Vol. 15; no. 1; pp. 1624 - 21
• Main Authors: Han, Kyung Ah, Yoon, Taek-Han, Kim, Jinhu, Lee, Jusung, Lee, Ju Yeon, Jang, Gyubin, Um, Ji Won, Kim, Jong Kyoung, Ko, Jaewon
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.02.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 38/1; 38/91; 42/41; 45/29; 45/77; 45/88; 631/378/340; 631/378/3920; 631/378/548/1964; 64/60; 82/58; 9/74; Ablation; Adhesion; Alternative splicing; Animals; Cell adhesion; Cell adhesion molecules; Cell Adhesion Molecules - metabolism; Circuits; Gene sequencing; Glutamic acid receptors (ionotropic); Hippocampus; Humanities and Social Sciences; Isoforms; Male; Mice; multidisciplinary; N-Methyl-D-aspartic acid receptors; Neural networks; Neurons; Neurons - metabolism; Physiology; Receptor-Like Protein Tyrosine Phosphatases, Class 2 - metabolism; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Signal Transduction; Synapses - metabolism; Synaptic transmission; Synaptic Transmission - physiology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-45695-0

LAR-RPTPs are evolutionarily conserved presynaptic cell-adhesion molecules that orchestrate multifarious synaptic adhesion pathways. Extensive alternative splicing of LAR-RPTP mRNAs may produce innumerable LAR-RPTP isoforms that act as regulatory “codes” for determining the identity and strength of specific synapse signaling. However, no direct evidence for this hypothesis exists. Here, using targeted RNA sequencing, we detected LAR-RPTP mRNAs in diverse cell types across adult male mouse brain areas. We found pronounced cell-type–specific patterns of two microexons, meA and meB, in Ptprd mRNAs. Moreover, diverse neural circuits targeting the same neuronal populations were dictated by the expression of different Ptprd variants with distinct inclusion patterns of microexons. Furthermore, conditional ablation of Ptprd meA + variants at presynaptic loci of distinct hippocampal circuits impaired distinct modes of synaptic transmission and object-location memory. Activity-triggered alterations of the presynaptic Ptprd meA code in subicular neurons mediates NMDA receptor-mediated postsynaptic responses in CA1 neurons and object-location memory. Our data provide the evidence of cell-type- and/or circuit-specific expression patterns in vivo and physiological functions of LAR-RPTP microexons that are dynamically regulated. LAR-RPTPs are presynaptic cell-adhesion proteins that regulate the synaptic properties. Here, LAR-RPTP microexon expression is profiled in region-, cell-type- and circuit-specific contexts and its physiological significance in encoding synaptic architecture is demonstrated.