Oligodendrocyte precursor cells modulate the neuronal network by activity-dependent ectodomain cleavage of glial NG2.
The role of glia in modulating neuronal network activity is an important question. Oligodendrocyte precursor cells (OPC) characteristically express the transmembrane proteoglycan nerve-glia antigen 2 (NG2) and are unique glial cells receiving synaptic input from neurons. The development of NG2+ OPC into myelinating oligodendrocytes has been well studied, yet the retention of a large population of synapse-bearing OPC in the adult brain poses the question as to additional functional roles of OPC in the neuronal network. Here we report that activity-dependent processing of NG2 by OPC-expressed secretases functionally regulates the neuronal network. NG2 cleavage by the α-secretase ADAM10 yields an ectodomain present in the extracellular matrix and a C-terminal fragment that is subsequently further processed by the γ-secretase to release an intracellular domain. ADAM10-dependent NG2 ectodomain cleavage and release (shedding) in acute brain slices or isolated OPC is increased by distinct activity-increasing stimuli. Lack of NG2 expression in OPC (NG2-knockout mice), or pharmacological inhibition of NG2 ectodomain shedding in wild-type OPC, results in a striking reduction of N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) in pyramidal neurons of the somatosensory cortex and alterations in the subunit composition of their α-amino-3-hydroxy-5-methyl-4-isoxazolepr opionicacid (AMPA) receptors. In NG2-knockout mice these neurons exhibit diminished AMPA and NMDA receptor-dependent current amplitudes; strikingly AMPA receptor currents can be rescued by application of conserved LNS protein domains of the NG2 ectodomain. Furthermore, NG2-knockout mice exhibit altered behavior in tests measuring sensorimotor function. These results demonstrate for the first time a bidirectional cross-talk between OPC and the surrounding neuronal network and demonstrate a novel physiological role for OPC in regulating information processing at neuronal synapses.
Molecular Cell Biology, Department of Biology, Johannes Gutenberg University Mainz, Mainz, Germany.
Dominik
D
Sakry
Institute of Physiology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany.
Angela
A
Neitz
Leibniz Institute for Neurobiology, Magdeburg, Germany.
Jeet
J
Singh
Leibniz Institute for Neurobiology, Magdeburg, Germany.
Renato
R
Frischknecht
Institute of Physiology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany.
Daniele
D
Marongiu
Molecular Cell Biology, Department of Biology, Johannes Gutenberg University Mainz, Mainz, Germany.
Fabien
F
Binamé
Molecular Cell Biology, Department of Biology, Johannes Gutenberg University Mainz, Mainz, Germany.
Sumudhu S
SS
Perera
Department of Psychiatry and Psychotherapy, University Medicine Mainz, Mainz, Germany.
Kristina
K
Endres
Institute of Physiological Chemistry, University Medical Center Mainz, Mainz, Germany.
Beat
B
Lutz
Mouse Behavior Outcome Unit, Focus Program Translational Neurosciences (FTN), Johannes Gutenberg University Mainz, Mainz, Germany.
Konstantin
K
Radyushkin
Molecular Cell Biology, Department of Biology, Johannes Gutenberg University Mainz, Mainz, Germany.
Jacqueline
J
Trotter
Institute of Physiology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany.
Thomas
T
Mittmann
D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D000941:Antigens / Q000378:metabolism*; D002460:Cell Line; D005109:Extracellular Matrix / Q000378:metabolism; D017774:Long-Term Potentiation; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism*; D009836:Oligodendroglia / Q000502:physiology*; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000378:metabolism*; D017966:Pyramidal Cells / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D055139:Sensory Gating; D013569:Synapses / Q000378:metabolism; D000099216:Chondroitin Sulfate Proteoglycan 4
D051722:ADAM Proteins; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases; D000941:Antigens; D008565:Membrane Proteins; D011509:Proteoglycans; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D000099216:Chondroitin Sulfate Proteoglycan 4; C491234:Adam10 protein, mouse