LRRC37B is a human modifier of voltage-gated sodium channels and axon excitability in cortical neurons
Baptiste Libé-Philippot, Amélie Lejeune, Keimpe Wierda, Nikolaos Louros, Emir Erkol, Ine Vlaeminck, Sofie Beckers, Vaiva Gaspariunaite, Angéline Bilheu, Katerina Konstantoulea, Hajnalka Nyitrai, Matthias De Vleeschouwer, Kristel M. Vennekens, Niels Vidal, Thomas W. Bird, Daniela C. Soto, Tom Jaspers, Maarten Dewilde, Megan Y. Dennis, Frederic Rousseau, Davide Comoletti, Joost Schymkowitz, Tom Theys, Joris de Wit, Pierre Vanderhaeghen
human brain evolution, gene duplicates, neuronal excitability, LRRC37, FGF13, voltage-gated channels, axon initial segment, cerebral cortex, SCN1B
The enhanced cognitive abilities characterizing the human species result from specialized features of neurons and circuits. Here, we report that the hominid-specific gene LRRC37B encodes a receptor expressed in human cortical pyramidal neurons (CPNs) and selectively localized to the axon initial segment (AIS), the subcellular compartment triggering action potentials. Ectopic expression of LRRC37B in mouse CPNs in vivo leads to reduced intrinsic excitability, a distinctive feature of some classes of human CPNs. Molecularly, LRRC37B binds to the secreted ligand FGF13A and to the voltage-gated sodium channel (Nav) β-subunit SCN1B. LRRC37B concentrates inhibitory effects of FGF13A on Nav channel function, thereby reducing excitability, specifically at the AIS level. Electrophysiological recordings in adult human cortical slices reveal lower neuronal excitability in human CPNs expressing LRRC37B. LRRC37B thus acts as a species-specific modifier of human neuron excitability, linking human genome and cell evolution, with important implications for human brain function and diseases.