| STUDY |
Deneris and his colleagues are trying to pierce that fog by identifying which genes are important in the development of the brain's serotonin neurons. They discovered a gene, designated Pet-1, that proves to be critical for the development and proper function of serotonin neurons. In mice that are genetically engineered to lack this gene, brain serotonin levels are only 1015% of the normal level [Neuron, 37, 233 (2003)]. As expected, Deneris says, the knockout mice exhibit heightened aggression and anxiety. Mouse aggression can be gauged by how staunchly males defend their territory. A "resident mouse" in its home cage will become perturbed if another male mouse–the "intruder" –is introduced into the cage, Deneris says. A wild-type resident mouse "will go up to the intruder, sniff it, groom it, and eventually may even attack the intruder by biting it, chasing it around the cage, and trying to get it out. So typically, there's a period of nonaggressive curiosity that can be followed by physical attack," Deneris says. The resident mouse "is being cautious about what it's doing. It's not being impulsive." Deneris measured the time it took for wild-type resident mice to attack intruder mice. Then he measured this "attack latency" for his Pet-1 knockout resident mice. "Our knockout mice spend a lot less time in nonviolent, exploratory behavior," he says. "They're very impulsive, and oftentimes they don't spend any time exploring. They don't spend any time thinking about what they're doing. They just go straight for the intruder and start to attack it." In addition, the knockout mice carry out more attacks and more severe attacks than the wild-type mice. "Our findings identify the first gene that impacts aggressive behavior in the adult through control of fetal serotonin neuron development," Deneris says. "The goal now is to determine the mechanisms through which the Pet-1-dependent genetic program regulates serotonergic modulation of aggression." He also plans to study "what has happened to the rest of the brain in the face of this low level of serotonin. Have the postsynaptic targets of serotonin neurons modulated themselves by either increasing or decreasing receptor expression?" That's not a simple question, given that the brain has more than a dozen types of serotonin receptors. The human and mouse serotonin systems share many features, and the same Pet-1 gene is present in the human genome. Thus, Deneris also wants to find out whether the human version of Pet-1 performs a similar function and whether naturally occurring genetic variants of the Pet-1 program exist and contribute to the risk for aggressive behaviors. |
| UPDATE | 06.03 |
| AUTHOR | Evan S. Deneris, associate professor of neuroscience at Case Western Reserve University School of Medicine, Cleveland. |
| LITERATURE REF. | [Neuron, 37, 233 (2003)]. |
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