Developing oligodendrocytes express functional GABA(B) receptors that stimulate cell proliferation and migration.
GABA(B) receptors (GABA(B)Rs) are involved in early events during neuronal development. The presence of GABA(B)Rs in developing oligodendrocytes has not been established. Using immunofluorescent co-localization, we have identified GABA(B)R proteins in O4 marker-positive oligodendrocyte precursor cells (OPCs) in 4-day-old mouse brain periventricular white matter. In culture, OPCs, differentiated oligodendrocytes (DOs) and type 2 astrocytes (ASTs) express both the GABA(B1abcdf) and GABA(B2) subunits of the GABA(B)R. Using semiquantitative PCR analysis with GABA(B)R isoform-selective primers we found that the expression level of GABA(B1abd) was substantially higher in OPCs or ASTs than in DOs. In contrast, the GABA(B2) isoform showed a similar level of expression in OPCs and DOs, and a significantly higher level in ASTs. This indicates that the expression of GABA(B1) and GABA(B2) subunits are under independent control during oligodendroglial development. Activation of GABA(B)Rs using the selective agonist baclofen demonstrated that these receptors are functionally active and negatively coupled to adenylyl cyclase. Manipulation of GABA(B)R activity had no effect on OPC migration in a conventional agarose drop assay, whereas baclofen significantly increased OPC migration in a more sensitive transwell microchamber-based assay. Exposure of cultured OPCs to baclofen increased their proliferation, providing evidence for a functional role of GABA(B)Rs in oligodendrocyte development. The presence of GABA(B)Rs in developing oligodendrocytes provides a new mechanism for neuronal-glial interactions during development and may offer a novel target for promoting remyelination following white matter injury.
Luyt
Karen
K
Medical Research Council Centre for Synaptic Plasticity, Department of Anatomy, University of Bristol, Bristol, UK.
Slade
Timothy P
TP
Dorward
Jienchi J
JJ
Durant
Claire F
CF
Wu
Yue
Y
Shigemoto
Ryuichi
R
Mundell
Stuart J
SJ
Váradi
Anikó
A
Molnár
Elek
E
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D018755:GABA Agonists / Q000494:pharmacology / Q000627:therapeutic use; D058786:GABA-B Receptor Agonists; D051379:Mice; D018345:Mice, Knockout; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018755:GABA Agonists; D058786:GABA-B Receptor Agonists; C485504:Gabbr2 protein, mouse; D021122:Protein Subunits; D012333:RNA, Messenger; D018080:Receptors, GABA-B; D005680:gamma-Aminobutyric Acid; D000262:Adenylyl Cyclases