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Local stimulation of protein synthesis by dopamine may also modify synapses in the brain during learning, says Erin Schuman.
The researchers then showed that Par-4 was produced in neurons where D2 receptors function. By knocking out Par-4 in mouse neurons or disrupting its interaction with the receptor, Tsai and Park caused striking behavioral changes in the mice. The knockout mice showed depression-like behaviors in multiple tests, easily giving up when faced with ordinary challenges.
"These are very exciting results for two reasons," Tsai says. "First, they indicate the importance of the signaling pathway mediated by the D2 receptor in depressive behavior. And second, this study pinpoints a specific pathway that implicates Par-4 in this process, which opens new possibilities for developing improved antidepressants."
Approaching dopamine from a different direction, HHMI investigator Erin M. Schuman and her colleague Bryan Smith, both at the California Institute of Technology, discovered how dopamine stimulates the synthesis of proteins in neuronal processes, which may in turn modify synapses in the brain during reward-related learning. The brain's reward circuitry is the top target of addictive drugs.
According to Schuman, scientists knew that dopamine influenced the strengthening of synaptic connections among neurons. This strengthening, or plasticity, causes activation of protein synthesis in the dendrites, which somehow leads to enhanced activity of other kinds of neurotransmitter receptors. However, Schuman says, no one knew how dopamine influences local protein synthesis and triggers plasticity.
Schuman, Smith, and their colleagues introduced the gene for a fluorescent reporter molecule into cultured rat neurons, so that the neurons glow during protein synthesis. When the researchers activated dopamine receptors on the dendrites, they detected the glow in the dendrites, revealing that dopamine activated local protein synthesis and, thus, promoted plasticity.
Additional experiments indicated that activation of dopamine receptors triggered immediate enhancement of synaptic transmission in the neurons. "That's a result that people have been seeking for years," says Schuman. "It's a very rapid effect on synaptic transmission that is protein synthesis-sensitive." The findings were published in the March 3, 2005, issue of Neuron.
According to Schuman, this research could have implications for understanding and treating drug addiction. "Over the past few years, investigators have begun to focus on the dendrite and its spines as potential sites that are altered during reward and addiction," she says. "This raises the possibility that some of the signaling that goes awry during addiction may have to do with local protein synthesis."
Photo: Misha Gravenor