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The Journal of Neuroscience, February 28, 2007, 27(9):2309-2317; doi:10.1523/JNEUROSCI.4565-06.2007

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Neurobiology of Disease
Development of Hydrocephalus in Mice Expressing the G_i-Coupled GPCR Ro1 RASSL Receptor in Astrocytes

Elizabeth J. Sweger,¹ Kristen B. Casper,¹ Kimberly Scearce-Levie,² Bruce R. Conklin,² and Ken D. McCarthy¹

¹Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, and ²Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California 94158

Correspondence should be addressed to Ken D. McCarthy, Department of Pharmacology, University of North Carolina at Chapel Hill, 1004 Mary Ellen Jones Building, CB# 7365, Chapel Hill, NC 27599-7365. Email: ken_mccarthy{at}med.unc.edu

We developed a transgenic mouse line that expresses the G_i-coupled RASSL (receptor activated solely by synthetic ligand) Ro1 in astrocytes to study astrocyte–neuronal communication. Surprisingly, we found that all transgenics expressing Ro1 developed hydrocephalus. We analyzed these mice in an effort to develop a new model of hydrocephalus that will further our understanding of the pathophysiology of the disease. Expression of Ro1 was restricted to astrocytes by crossing the transgenic hGFAP-tTA (tet transactivator behind the human glial fibrillary acidic protein promoter) mouse line with the transgenic tetO-Ro1/tetO-LacZ mouse line. This cross produced double-transgenic mice that expressed Ro1 in astrocytes. All double transgenics developed hydrocephalus by postnatal day 15, whereas single-transgenic littermate controls appeared normal. Hydrocephalic Ro1 mice displayed enlarged ventricles, partial denudation of the ependymal cell layer, altered subcommissural organ morphology, and obliteration of the cerebral aqueduct. Severely hydrocephalic mice also had increased levels of phospho-Erk and GFAP expression. Administration of doxycycline to breeding pairs suppressed Ro1 expression and the onset of hydrocephalus in double-transgenic offspring. Ro1 animals maintained on dox did not develop hydrocephalus; however, if taken off doxycycline at weaning, double-transgenic mice developed enlarged ventricles within 7 weeks, indicating that Ro1 expression also induces hydrocephalus in adults. This study discovered a new model of hydrocephalus in which the rate of pathogenesis can be controlled enabling the study of the pathogenesis of both juvenile and adult onset hydrocephalus.

Key words: astrocyte; hydrocephalus; opioid; G_i; RASSL; SCO; tetracycline

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Received May 12, 2006; revised Dec. 18, 2006; accepted Dec. 24, 2006.

Correspondence should be addressed to Ken D. McCarthy, Department of Pharmacology, University of North Carolina at Chapel Hill, 1004 Mary Ellen Jones Building, CB# 7365, Chapel Hill, NC 27599-7365. Email: ken_mccarthy{at}med.unc.edu

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