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

doi:10.1016/j.cell.2023.11.028

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 RousseauDavide Comoletti, Joost Schymkowitz, Tom Theys, Joris de Wit, Pierre Vanderhaeghen

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (US)
Pages (from-to)	5766-5783.e25
Journal	Cell
Volume	186
Issue number	26
DOIs	https://doi.org/10.1016/j.cell.2023.11.028
State	Published - Dec 21 2023

Keywords

FGF13
LRRC37
SCN1B
axon initial segment
cerebral cortex
gene duplicates
human brain evolution
neuronal excitability
voltage-gated channels

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2023.11.028

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Libé-Philippot, B., Lejeune, A., Wierda, K., Louros, N., Erkol, E., Vlaeminck, I., Beckers, S., Gaspariunaite, V., Bilheu, A., Konstantoulea, K., Nyitrai, H., De Vleeschouwer, M., Vennekens, K. M., Vidal, N., Bird, T. W., Soto, D. C., Jaspers, T., Dewilde, M., Dennis, M. Y., ... Vanderhaeghen, P. (2023). LRRC37B is a human modifier of voltage-gated sodium channels and axon excitability in cortical neurons. Cell, 186(26), 5766-5783.e25. https://doi.org/10.1016/j.cell.2023.11.028

Libé-Philippot, B, Lejeune, A, Wierda, K, Louros, N, Erkol, E, Vlaeminck, I, Beckers, S, Gaspariunaite, V, Bilheu, A, Konstantoulea, K, Nyitrai, H, De Vleeschouwer, M, Vennekens, KM, Vidal, N, Bird, TW, Soto, DC, Jaspers, T, Dewilde, M, Dennis, MY, Rousseau, F, Comoletti, D, Schymkowitz, J, Theys, T, de Wit, J & Vanderhaeghen, P 2023, 'LRRC37B is a human modifier of voltage-gated sodium channels and axon excitability in cortical neurons', Cell, vol. 186, no. 26, pp. 5766-5783.e25. https://doi.org/10.1016/j.cell.2023.11.028

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title = "LRRC37B is a human modifier of voltage-gated sodium channels and axon excitability in cortical neurons",

abstract = "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.",

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doi = "10.1016/j.cell.2023.11.028",

language = "English (US)",

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T1 - LRRC37B is a human modifier of voltage-gated sodium channels and axon excitability in cortical neurons

AU - Libé-Philippot, Baptiste

AU - Lejeune, Amélie

AU - Wierda, Keimpe

AU - Louros, Nikolaos

AU - Erkol, Emir

AU - Vlaeminck, Ine

AU - Beckers, Sofie

AU - Gaspariunaite, Vaiva

AU - Bilheu, Angéline

AU - Konstantoulea, Katerina

AU - Nyitrai, Hajnalka

AU - De Vleeschouwer, Matthias

AU - Vennekens, Kristel M.

AU - Vidal, Niels

AU - Bird, Thomas W.

AU - Soto, Daniela C.

AU - Jaspers, Tom

AU - Dewilde, Maarten

AU - Dennis, Megan Y.

AU - Rousseau, Frederic

AU - Comoletti, Davide

AU - Schymkowitz, Joost

AU - Theys, Tom

AU - de Wit, Joris

AU - Vanderhaeghen, Pierre

PY - 2023/12/21

Y1 - 2023/12/21

N2 - 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.

AB - 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.

KW - FGF13

KW - LRRC37

KW - SCN1B

KW - axon initial segment

KW - cerebral cortex

KW - gene duplicates

KW - human brain evolution

KW - neuronal excitability

KW - voltage-gated channels

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DO - 10.1016/j.cell.2023.11.028

M3 - Article

C2 - 38134874

AN - SCOPUS:85180605324

SN - 0092-8674

VL - 186

SP - 5766-5783.e25

JO - Cell

JF - Cell

IS - 26

ER -

LRRC37B is a human modifier of voltage-gated sodium channels and axon excitability in cortical neurons

Abstract

Keywords

ASJC Scopus subject areas

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