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The Journal of Neuroscience, November 22, 2006, 26(47):12339-12350; doi:10.1523/JNEUROSCI.3573-06.2006

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Neurobiology of Disease
Mice with Conditional Inactivation of Fibroblast Growth Factor Receptor-2 Signaling in Oligodendrocytes Have Normal Myelin But Display Dramatic Hyperactivity when Combined with Cnp1 Inactivation

Y. Kaga,¹ W. J. Shoemaker,² M. Furusho,¹ M. Bryant,¹ J. Rosenbluth,³ S. E. Pfeiffer,¹ L. Oh,¹ M. Rasband,¹ C. Lappe-Siefke,⁴ K. Yu,⁵ D. M. Ornitz,⁵ K.-A. Nave,⁴ and R. Bansal¹

Departments of ¹Neuroscience and ²Psychiatry, University of Connecticut Medical School, Farmington, Connecticut 06030, ³Department of Physiology and Neuroscience, New York University School of Medicine, New York, New York 10003, ⁴Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Goettingen, Germany, and ⁵Department of Molecular Biology and Cell Biology, Washington University School of Medicine, St. Louis, Missouri 63110

Correspondence should be addressed to Dr. Rashmi Bansal, Department of Neuroscience, University of Connecticut Medical School, 263 Farmington Avenue, Farmington, CT 06030-3401. Email: bansal{at}neuron.uchc.edu

Fibroblast growth factor receptors (Fgfr) comprise a widely expressed family of developmental regulators implicated in oligodendrocyte (OL) maturation of the CNS. Fgfr2 is expressed by OLs in myelinated fiber tracks. In vitro, Fgfr2 is highly upregulated during OL terminal differentiation, and its activation leads to enhanced growth of OL processes and the formation of myelin-like membranes. To investigate the in vivo function of Fgfr2 signaling by myelinating glial cells, we inactivated the floxed Fgfr2 gene in mice that coexpress Cre recombinase (cre) as a knock-in gene into the OL-specific 2',3'-cyclic nucleotide phosphodiesterase (Cnp1) locus. Surprisingly, no obvious defects were detected in brain development of these conditional mutants, including the number of OLs, the onset and extent of myelination, the ultrastructure of myelin, and the expression level of myelin proteins. However, unexpectedly, a subset of these conditional Fgfr2 knock-out mice that are homozygous for cre and therefore are also Cnp1 null, displayed a dramatic hyperactive behavior starting at 2 weeks of age. This hyperactivity was abolished by treatment with dopamine receptor antagonists or catecholamine biosynthesis inhibitors, suggesting that the symptoms involve a dysregulation of the dopaminergic system. Although the molecular mechanisms are presently unknown, this novel mouse model of hyperactivity demonstrates the potential involvement of OLs in neuropsychiatric disorders, as well as the nonpredictable role of genetic interactions in the behavioral phenotype of mice.

Key words: oligodendrocyte; myelin; FGF receptor; CNP; fibroblast growth factor; 2',3'-cyclic nucleotide phosphodiesterase

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Received June 5, 2006; revised Oct. 13, 2006; accepted Oct. 17, 2006.

Correspondence should be addressed to Dr. Rashmi Bansal, Department of Neuroscience, University of Connecticut Medical School, 263 Farmington Avenue, Farmington, CT 06030-3401. Email: bansal{at}neuron.uchc.edu

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