|ZFIN ID: ZDB-PUB-090706-21|
Ethanol-modulated camouflage response screen in zebrafish uncovers a novel role for cAMP and extracellular signal-regulated kinase signaling in behavioral sensitivity to ethanol
Peng, J., Wagle, M., Mueller, T., Mathur, P., Lockwood, B.L., Bretaud, S., and Guo, S.
|Source:||The Journal of neuroscience : the official journal of the Society for Neuroscience 29(26): 8408-8418 (Journal)|
|Registered Authors:||Guo, Su, Mathur, Priya, Mueller, Thomas, Peng, Jisong, Wagle, Mahendra|
|PubMed:||19571131 Full text @ J. Neurosci.|
Peng, J., Wagle, M., Mueller, T., Mathur, P., Lockwood, B.L., Bretaud, S., and Guo, S. (2009) Ethanol-modulated camouflage response screen in zebrafish uncovers a novel role for cAMP and extracellular signal-regulated kinase signaling in behavioral sensitivity to ethanol. The Journal of neuroscience : the official journal of the Society for Neuroscience. 29(26):8408-8418.
ABSTRACTEthanol, a widely abused substance, elicits evolutionarily conserved behavioral responses in a concentration-dependent manner in vivo. The molecular mechanisms underlying such behavioral sensitivity to ethanol are poorly understood. While locomotor-based behavioral genetic screening is successful in identifying genes in invertebrate models, such complex behavior-based screening has proven difficult for recovering genes in vertebrates. Here we report a novel and tractable ethanol response in zebrafish. Using this ethanol-modulated camouflage response as a screening assay, we have identified a zebrafish mutant named fantasma (fan), which displays reduced behavioral sensitivity to ethanol. Positional cloning reveals that fan encodes type 5 adenylyl cyclase (AC5). fan/ac5 is required to maintain the phosphorylation of extracellular signal-regulated kinase (ERK) in the forebrain structures, including the telencephalon and hypothalamus. Partial inhibition of phosphorylation of ERK in wild-type zebrafish mimics the reduction in sensitivity to stimulatory effects of ethanol observed in the fan mutant, whereas, strikingly, strong inhibition of phosphorylation of ERK renders a stimulatory dose of ethanol sedating. Since previous studies in Drosophila and mice show a role of cAMP signaling in suppressing behavioral sensitivity to ethanol, our findings reveal a novel, isoform-specific role of AC signaling in promoting ethanol sensitivity, and suggest that the phosphorylation level of the downstream effector ERK is a critical "gatekeeper" of behavioral sensitivity to ethanol.