Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders

doi:10.1073/pnas.0702157104

Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders

*Neurobiology Program, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115;
^†PsychoGenics, Inc., Tarrytown, NY 10591;
^¶Department of Biopsychology, New York State Psychiatric Institute, New York, NY 10032;
^‡Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201; and
^§Department of Psychiatry, Columbia University, New York, NY 10032

Communicated by Louis M. Kunkel, Harvard Medical School, Boston, MA, March 9, 2007 (received for review December 19, 2006)

Abstract

Several psychiatric disorders are associated with white matter defects, suggesting that oligodendrocyte (OL) abnormalities underlie some aspects of these diseases. Neuregulin 1 (NRG1) and its receptor, erbB4, are genetically linked with susceptibility to schizophrenia and bipolar disorder. In vitro studies suggest that NRG1-erbB signaling is important for OL development. To test whether erbB signaling contributes to psychiatric disorders by regulating the structure or function of OLs, we analyzed transgenic mice in which erbB signaling is blocked in OLs in vivo. Here we show that loss of erbB signaling leads to changes in OL number and morphology, reduced myelin thickness, and slower conduction velocity in CNS axons. Furthermore, these transgenic mice have increased levels of dopamine receptors and transporters and behavioral alterations consistent with neuropsychiatric disorders. These results indicate that defects in white matter can cause alterations in dopaminergic function and behavior relevant to neuropsychiatric disorders.

Footnotes

^‖To whom correspondence should be addressed at:
Neurobiology Program, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115.
E-mail: gabriel.corfas{at}childrens.harvard.edu
Author contributions: K.R. and J.C.M. contributed equally to this work; K.R., J.C.M., C.C., P.O., D.B., and G.C. designed research; K.R., J.C.M., B.F.E., N.E., S.P.S., B.M.H., M.B.-M., and H.M. performed research; K.R., J.C.M., B.F.E., D.B., and G.C. analyzed data; and K.R., J.C.M., and G.C. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0702157104/DC1
Abbreviations:

Tg,

transgenic;

OL,

oligodendrocyte;

NRG1,

neuregulin 1;

DHX,

dihydrexidine;

DAT,

dopamine transporter;

CNP,

2′,3′-cyclic nucleotide 3′-phosphodiesterase;

PLP,

proteolipid protein.