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The Journal of Neuroscience, October 10, 2007, 27(41):10982-10992; doi:10.1523/JNEUROSCI.0793-07.2007

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Development/Plasticity/Repair
Inhibition of Rho via Arg and p190RhoGAP in the Postnatal Mouse Hippocampus Regulates Dendritic Spine Maturation, Synapse and Dendrite Stability, and Behavior

Mindan K. Sfakianos,¹ Aaron Eisman,^1 * Shannon L. Gourley,^2,3 * William D. Bradley,^1 * Alfred J. Scheetz,¹ Jeffrey Settleman,⁶ Jane R. Taylor,^2,3 Charles A. Greer,^2,4,5 Anne Williamson,⁴ and Anthony J. Koleske^1,2,5

¹Department of Molecular Biophysics and Biochemistry, ²Interdepartmental Neuroscience Program, and Departments of ³Psychiatry, ⁴Neurosurgery, and ⁵Neurobiology, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, Connecticut 06520, and ⁶Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129

Correspondence should be addressed to Dr. Anthony J. Koleske, Department of Molecular Biophysics and Biochemistry, 333 Cedar Street SHMC-E31, Yale University School of Medicine, New Haven, CT 06520. Email: anthony.koleske{at}yale.edu

The RhoA (Rho) GTPase is a master regulator of dendrite morphogenesis. Rho activation in developing neurons slows dendrite branch dynamics, yielding smaller, less branched dendrite arbors. Constitutive activation of Rho in mature neurons causes dendritic spine loss and dendritic regression, indicating that Rho can affect dendritic structure and function even after dendrites have developed. However, it is unclear whether and how endogenous Rho modulates dendrite and synapse morphology after dendrite arbor development has occurred. We demonstrate that a Rho inhibitory pathway involving the Arg tyrosine kinase and p190RhoGAP is essential for synapse and dendrite stability during late postnatal development. Hippocampal CA1 pyramidal dendrites develop normally in arg^–/– mice, reaching their mature size by postnatal day 21 (P21). However, dendritic spines do not undergo the normal morphological maturation in these mice, leading to a loss of hippocampal synapses and dendritic branches by P42. Coincident with this synapse and dendrite loss, arg^–/– mice exhibit progressive deficits in a hippocampus-dependent object recognition behavioral task. p190RhoGAP localizes to dendritic spines, and its activity is reduced in arg^–/– hippocampus, leading to increased Rho activity. Although mutations in p190rhogap enhance dendritic regression resulting from decreased Arg levels, reducing gene dosage of the Rho effector ROCKII can suppress the dendritic regression observed in arg^–/– mice. Together, these data indicate that signaling through Arg and p190RhoGAP acts late during synaptic refinement to promote dendritic spine maturation and synapse/dendrite stability by attenuating synaptic Rho activity.

Key words: Arg tyrosine kinase; dendrite; synapse; hippocampus; p190RhoGAP; Rho

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Received Feb. 21, 2007; revised Aug. 24, 2007; accepted Aug. 25, 2007.

Correspondence should be addressed to Dr. Anthony J. Koleske, Department of Molecular Biophysics and Biochemistry, 333 Cedar Street SHMC-E31, Yale University School of Medicine, New Haven, CT 06520. Email: anthony.koleske{at}yale.edu

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