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The Journal of Neuroscience, January 18, 2006, 26(3):742-756; doi:10.1523/JNEUROSCI.4478-05.2006

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Development/Plasticity/Repair
Reversal of Neuronal Migration in a Mouse Model of Fetal Alcohol Syndrome by Controlling Second-Messenger Signalings

Tatsuro Kumada,¹ Madepalli K. Lakshmana,¹ and Hitoshi Komuro^1,2

¹Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, and ²Department of Molecular Medicine, The Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195

The brains of fetal alcohol syndrome patients exhibit impaired neuronal migration, but little is known about the mechanisms underlying this abnormality. Here we show that Ca²⁺ signaling and cyclic nucleotide signaling are the central targets of alcohol action in neuronal cell migration. Acute administration of ethanol reduced the frequency of transient Ca²⁺ elevations in migrating neurons and cGMP levels and increased cAMP levels. Experimental manipulations of these second-messenger pathways, through stimulating Ca²⁺ and cGMP signaling or inhibiting cAMP signaling, completely reversed the action of ethanol on neuronal migration in vitro as well as in vivo. Each second messenger has multiple but distinct downstream targets, including Ca²⁺/calmodulin-dependent protein kinase II, calcineurin, protein phosphatase 1, Rho GTPase, mitogen-activated protein kinase, and phosphoinositide 3-kinase. These results demonstrate that the aberrant migration of immature neurons in the fetal brain caused by maternal alcohol consumption may be corrected by controlling the activity of these second-messenger pathways.

Key words: cerebellar development; granule cell; neuronal cell migration; cAMP; cGMP; rate of cell movement

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Received Sep 23, 2005; revised November 18, 2005; accepted November 20, 2005.

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