RT Journal Article
SR Electronic
T1 Ethanol-Modulated Camouflage Response Screen in Zebrafish Uncovers a Novel Role for cAMP and Extracellular Signal-Regulated Kinase Signaling in Behavioral Sensitivity to Ethanol
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 8408
OP 8418
DO 10.1523/JNEUROSCI.0714-09.2009
VO 29
IS 26
A1 Jisong Peng
A1 Mahendra Wagle
A1 Thomas Mueller
A1 Priya Mathur
A1 Brent L. Lockwood
A1 Sandrine Bretaud
A1 Su Guo
YR 2009
UL http://www.jneurosci.org/content/29/26/8408.abstract
AB Ethanol, 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.