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Friday, July 9, 2010

siRNA-mediated GABAB receptor at early fetal rat brain upon acute and chronic ethanol exposure: Down regulation of PKA and p-CREB expression



To observe the modulatory role of GABAB1R upon ethanol's effect during early brain development, we studied the effects of chronic maternal (10% ethanol during pregnancy) and acute (in vitro) ethanol exposure on the neuronal protein kinase A (PKA-) and phosphorylation of cAMP-response element binding protein (p-CREB), using a system where GABAB1R were specifically knocked down in the primary cells cultured at gestational day (GD) 12.5.

The results showed that upon acute and chronic ethanol treatment the GABAB1R expression was decreased and further decreased when GABAB1R was transfection with siRNA, while increased upon exposure of baclofen, and baclofen plus phaclofen treatment.

PKA expression was also decreased with acute and chronic ethanol treatment, whereas it showed increase upon exposure of baclofen and baclofen with phaclofen.

Furthermore, intracellular Ca2+ concentration was increased upon ethanol, baclofen, phaclofen exposure but showed decrease in GABAB1R siRNA group.

Finally, these effects could lead to changes of p-CREB expression, which showed same expression pattern as PKA.

We speculate that GABABR activity upon ethanol exposure could modulate intracellular calcium homeostasis and the expressional changes of PKA and p-CREB, which cause various negative effects on fetal brain development and modulation of GABABR upon ethanol exposure may underlying cause of ethanol's effects.


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