Inhibition of cerebellar granule cell turning by alcohol

Abstract

Ectopic neurons are often found in the brains of fetal alcohol spectrum disorders (FASD) and fetal alcohol syndrome (FAS) patients, suggesting that alcohol exposure impairs neuronal cell migration. Although it has been reported that alcohol decreases the speed of neuronal cell migration, little is known about whether alcohol also affects the turning of neurons. Here we show that ethanol exposure inhibits the turning of cerebellar granule cells in vivo and in vitro. First, in vivo studies using P10 mice demonstrated that a single i.p. injection of ethanol not only reduces the number of turning granule cells but also alters the mode of turning at the EGL-ML border of the cerebellum. Second, in vitro analysis using microexplant cultures of P0-P3 mouse cerebella revealed that ethanol directly reduces the frequency of spontaneous granule cell turning in a dosedependent manner. Third, the action of ethanol on the frequency of granule cell turning was significantly ameliorated by stimulating Ca 2+ and cGMP signaling or by inhibiting cAMP signaling. Taken together, these results indicate that ethanol affects the frequency and mode of cerebellar granule cell turning through alteration of the Ca 2+ and cyclic nucleotide signaling pathways, suggesting that the abnormal allocation of neurons found in the brains of FASD and FSA patients results, at least in part, from impaired turning of immature neurons by alcohol.

Forebrain and hindbrain development in zebrafish is sensitive to ethanol exposure involving agrin, Fgf, and sonic hedgehog function

“…Because we observed a decreased expression of the granule cell progenitor marker Atonal1a at early ages, as well as a delay in its expression, it is possible that ethanol exposure during zebrafish CNS development is both decreasing the number of granule cell progenitors, as well as causing a delay in the differentiation of granule cells, as was observed with GABAergic Purkinje cells. It is also possible that migration of Atonal1a-positive granule cell progenitors to the cerebellum is impaired by ethanol exposure, and studies in rodents show that ethanol exposure perturbs granule cell migration from the external granule cell layer (Gonzalez-Burgos and Alejandre-Gomez, 1995; Kumada et al, 2010;Luo, 2010). In preliminary studies, we have analyzed BrdU incorporation by rhombic lip cells, and these data suggest that ethanol exposure may be decreasing cell proliferation in the rhombic lip (data not shown).…”

Does moderate drinking harm the fetal brain? Insights from animal models

“…Exposure of rats through gestation and weaning (voluntary drinking; BAL = 0.07 g/dl) increased soma size and dendritic length in cerebellar granule cells, and delayed maturation of Bergmann glia [47]. Moreover, a recent study reported alterations in cerebellar granule cell migration in a mouse model of ethanol exposure during the 3 rd trimester-equivalent (1 g/kg intraperitoneal injection at P10; BAL = 0.07 g/dl) [48]. In addition, 3 rd trimester-equivalent exposure (1-2 g/kg/day P2-11; intragastric intubation; BAL = 0.05-0.15 g/dl) impaired eyeblink conditioning in adult rats, which could be related to alterations in deep cerebellar nuclear neurons [49].…”

“…Voluntary drinking has also been used to expose monkeys to ethanol at different stages of pregnancy [62]. B) To model human exposure during the 3 rd trimester, rat pups and dams were exposed via ethanol vapor inhalation chambers [35, 55] or C) pups via intraperitoneal or subcutaneous ethanol injections [48, 64]. …”

Light stimuli control neuronal migration by altering of insulin-like growth factor 1 (IGF-1) signaling

“…During the last 2 decades, real-time observation of cell movement demonstrated that granule cells display a distinct mode, tempo, and rate of migration as they traverse different cortical layers (13)(14)(15)(16)(17). It became apparent that granule cell migration is controlled by the orchestrated activity of multiple molecular events at the right time and right place, including pathway selection, activation of specific receptors and channels, and assembly and disassembly of cytoskeletal components (18)(19)(20)(21)(22).…”