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

Abstract

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 Ca 2ϩ 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 Ca 2ϩ elevations in migrating neurons and cGMP levels and increased cAMP levels. Experimental manipulations of these second-messenger pathways, through stimulating Ca 2ϩ 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 Ca 2ϩ /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.

Signaling Pathways Regulating Cell Motility: A Role in Ethanol Teratogenicity?

“…These potentially important targets of ethanol include widely recognized second messengers like Ca 2+ , cyclic nucleotides, and the Rho family GTPases. Indeed, results published during the preparation of this symposium summary demonstrated the central role of Ca 2+ , cAMP, and cGMP in the inhibition of cerebellar granule cell migration by acute ethanol exposure (Kumada et al, 2006). Future studies should attempt to take into account overlapping signaling pathways with shared signaling intermediates for neuronal migration, axon growth and axon guidance that have also been identified as targets of ethanol in neurons and nonneuronal cells.…”

Excess of serotonin affects embryonic interneuron migration through activation of the serotonin receptor 6

“…The effect of EMD 386088 (100 mM) was abolished after co-application of SB 258585 (100 mM), a potent and selective 5-HT6 receptor antagonist (Figure 5d), 27 indicating that the effect of EMD 386088 on migration was specific for the 5-HT6 receptor. The migratory effects of 5-HT6 receptor activation appeared to be specific, as application of SR 57227 (200 mM), a selective 5-HT3 agonist, Given that 5-HT6 receptor activation has been shown to increase cyclic adenosine monophosphate (cAMP) levels, we tested the effect of forskolin (30 mM), a stimulator of the adenylyl cyclase 29 and observed a significant decrease in the mean migratory speed of interneurons after forskolin application (Figure 6a). Furthermore, we observed that forskolin Excess of serotonin affects interneuron migration O Riccio et al application (30 mM) significantly increased the effect of EMD 386088 (100 mM) on interneuron migration (Figure 6a).…”

“…Furthermore, we observed that forskolin Excess of serotonin affects interneuron migration O Riccio et al application (30 mM) significantly increased the effect of EMD 386088 (100 mM) on interneuron migration (Figure 6a). Conversely, application of Rp-cAMPS (200 mM), a nonhydrolyzable analogue of cAMP and antagonist of protein kinase A, 29 significantly reduced the effect of EMD 386088 (200 mM) on migration (Figure 6b). Taken together these results indicate that modulation of the cAMP signaling pathway can amplify or inhibit the migratory effects due to 5-HT6 activation, suggesting that the cAMP signaling pathway is implicated in the migratory effects observed after 5-HT6 receptor activation.…”

Rescue of neuronal migration deficits in a mouse model of fetal Minamata disease by increasing neuronal Ca2+spike frequency

“…The effects of MeHg on Ca 2+ spike frequency in granule cell somata were dose dependent (Fig. 3B) , cAMP, and IGF1 signaling because it has been reported that these signaling pathways are involved in the control of Ca 2+ spike frequency (30,31,33) and are affected by MeHg exposure (20,34,35). We used 10 μM MeHg, because the application of this amount of MeHg induces a significant deceleration of the speed of granule cell migration (Fig.…”