Calcium-Stimulated Adenylyl Cyclases Modulate Ethanol-Induced Neurodegeneration in the Neonatal Brain

Abstract

Fetal alcohol exposure results in cognitive and neurobehavioral deficits, but the effects of modifying genetic loci on the severity of these sequelas have not been well characterized. Although the cAMP signaling pathway has been shown to be an important modulator of ethanol sensitivity in adult mice, its potential role in modulating ethanol-induced neurodegeneration has not been examined. Adenylyl cyclases (ACs) 1 and 8 produce cAMP in response to intracellular calcium elevation and modulate several aspects of neuronal function, including ethanol sensitivity. AC1 and AC8 are expressed widely throughout the brain of neonatal mice, and genetic deletion of both AC1 and AC8 in double-knock-out (DKO) mice enhances ethanol-induced neurodegeneration in the brains of neonatal mice. In addition, ethanol treatment induces significantly greater levels of caspase-3 activation in the brains of DKO mice compared with wild-type (WT) mice, reflecting higher numbers of apoptotic neurons. Administration of the NMDA receptor antagonist MK801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine hydrogen maleate] or the GABA(A) receptor potentiator phenobarbital, which mimics components of the effects of ethanol on neurons, results in significantly greater neurodegeneration in the brains of neonatal DKO mice than WT mice. Furthermore, loss of a single calcium-stimulated AC isoform potentiates neurodegeneration after administration of ethanol, MK801, or phenobarbital. In contrast, the levels of physiological cell death, death after hypoxia/ischemia, and excitotoxic cell death are not increased in the brains of DKO mice. Thus, AC1 and AC8 are critical modulators of neurodegeneration induced by activity blockade in the neonatal brain and represent genetic loci that may potentially modify the severity of fetal alcohol syndrome.

Widespread Neonatal Brain Damage following Calcium Channel Blockade

“…Further, neurons sensitive to agents such as MK801 or nimodipine may be generally sensitive to agents or events that alter intracellular calcium, reflecting an inability to buffer changes in calcium at P7 (but not at later ages) that makes these neurons selectively vulnerable. That reduction in intracellular calcium plays some role in mediating the age-dependent toxicities we describe here is supported by evidence showing calcium-sensitive adenylate cyclases are downstream targets following NM-DAR blockade [Maas et al, 2005]. Further, recent observations in our lab indicate that MK801-induced activated caspase-3-ir is inversely related to expression of calcium binding proteins [Lema Tome et al, in press].…”

Ethanol Induces Apoptotic Death of Developing β-Endorphin Neurons via Suppression of Cyclic Adenosine Monophosphate Production and Activation of Transforming Growth Factor-β1-Linked Apoptotic Signaling

“…We have chosen these isoforms of AC because our preliminary study identified AC6, -7, and -8 as the major isoforms of AC in the hypothalamic cells that are ethanol-sensitive (Yoshimura and Tabakoff, 1999;Chandler et al, 2004;Maas et al, 2005). We have also determined the effect of the cAMP analog dbcAMP on ethanol-induced alterations in the number of ␤-EP neurons and TUNEL-positive ␤-EP neurons in hypothalamic cell cultures.…”

Restoration of Neuronal Plasticity by a Phosphodiesterase Type 1 Inhibitor in a Model of Fetal Alcohol Exposure

“…VINP treatment is likely to increase cAMP signaling, which in turn would enhance the activity of a large number of factors downstream from the NMDA receptor, any of which may be downregulated in FAS. In fact, it has been suggested that an alteration in the cAMP cascade may play an important role in the deleterious effects of early alcohol exposure on brain development (Maas et al, 2005). A possible explanation for an alteration of cAMP levels after early alcohol exposure is related to the upregulation of calmodulin (CaM) that has been demonstrated to occur after chronic alcohol exposure (Pant et al, 1985;Hamoudi et al, 1995).…”