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PLoS Biol. 2014 Nov 11;12(11):e1001993. doi: 10.1371/journal.pbio.1001993. eCollection 2014 Nov.

Oligodendrocyte precursor cells modulate the neuronal network by activity-dependent ectodomain cleavage of glial NG2.

Author information

1
Molecular Cell Biology, Department of Biology, Johannes Gutenberg University Mainz, Mainz, Germany.
2
Institute of Physiology, University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany.
3
Leibniz Institute for Neurobiology, Magdeburg, Germany.
4
Department of Psychiatry and Psychotherapy, University Medicine Mainz, Mainz, Germany.
5
Institute of Physiological Chemistry, University Medical Center Mainz, Mainz, Germany.
6
Mouse Behavior Outcome Unit, Focus Program Translational Neurosciences (FTN), Johannes Gutenberg University Mainz, Mainz, Germany.

Abstract

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.

Comment in

PMID:
25387269
PMCID:
PMC4227637
DOI:
10.1371/journal.pbio.1001993
[Indexed for MEDLINE]
Free PMC Article

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