March 03, 2005
A Rewarding Discovery Shows How Dopamine Activates Brain Circuitry
Researchers have discovered how dopamine — a molecule important for
communication between neurons in the brain — stimulates the synthesis
of proteins in neuronal processes. This local stimulation of protein
synthesis may modify synapses in the brain during learning, said the
researchers.
The new findings add to the understanding of dopamine's influence on
the brain's reward circuitry that appears to be altered by addictive
drugs. The research team, led by Erin M. Schuman, a Howard Hughes
Medical Institute investigator at the California Institute of
Technology, published its findings in the March 3, 2005, issue of the
journal Neuron. Lead author on the paper was Bryan Smith in
Schuman's laboratory.
“This raises the possibility that some of the signaling that goes awry during addiction may have to do with local protein synthesis.”
Erin M. Schuman
Neurons trigger nerve impulses in their neighbors by launching
bursts of neurotransmitters, such as glutamate and dopamine, across
junctions called synapses. The neurotransmitter receiving stations on
neurons are tiny spines that festoon the surfaces of dendrites, which
are small branches that extend from neurons.
“Dopamine and regulation of dopamine signaling is important
for reward circuits in the brain, including those responsible for our
ability to learn about the positive or negative consequences of
environmental stimuli including drugs of abuse,” said Schuman.
Dopamine-triggered neuronal signaling is also involved in regulating
motivation, and in such diseases as Parkinson's disease and
schizophrenia, she said.
According to Schuman, it was known that dopamine influenced the
strengthening of synaptic connections among neurons. It was also known
that such strengthening, or plasticity, involved activation of protein
synthesis in the dendrites, which somehow led to enhanced activity of
other kinds of neurotransmitter receptors. However, she said, the
mechanism by which dopamine influenced such local protein synthesis and
triggered plasticity was not known.
In their studies, Schuman and her colleagues introduced the gene for
a fluorescent “reporter” molecule into cultured rat
neurons, such that when protein synthesis was activated, the neurons
would emit a telltale glow. When the researchers activated dopamine
receptors on the dendrites, they detected the glow in the dendrites,
revealing that dopamine did activate local protein synthesis and, thus,
promoted plasticity. In a more targeted experiment, they introduced
molecules directly into the dendrites that would tag newly synthesized
endogenous proteins fluorescently. Those experiments also revealed
local protein synthesis due to activation of dopamine receptors.
The researchers' measurements indicated that dopamine receptor
activation triggered immediate enhancement of
protein-synthesis-sensitive synaptic transmission among the neurons.
“That's a result that people have been seeking for years,”
said Schuman. “It's a very rapid effect on synaptic transmission
that is protein-synthesis-sensitive.”
Schuman and her colleagues also identified a specific
neurotransmitter receptor subunit whose synthesis was switched on by
dopamine-triggered plasticity. That subunit, called GluR1, is part of
another class of neurotransmitter receptors, called AMPA receptors —
which play a key role in normal synaptic transmission and the
plasticity associated with learning and memory. The researchers
demonstrated that dopamine caused an increase in the GluR1 subunit
delivery to the cell membrane, where it would be expected to play a
role in enhancing responsiveness to transmitter.
“This evidence is consistent with the concept of the `silent
synapse,'” said Schuman. “That idea holds that such
synapses are functionally silent because they do not possess functional
AMPA-type receptors. Rather, these silent synapses possess only
receptors known as NMDA-type receptors, which are thought to be
inactive. However, when AMPA-type receptors are inserted into the
membrane, according to this theory, a silent synapse converts to an
active one.”
The researchers also demonstrated a link between dopamine-related
plasticity and NMDA receptor activity. They found that when they
blocked NMDA receptors, the dopamine-regulated synthesis of GluR1, as
well as enhanced synaptic transmission, were blocked. “This
experiment showed that there may be some specificity to dopamine's
actions, at least in how it stimulated local protein synthesis,”
said Schuman. “You may need both dopamine release and functional
NMDA receptors to trigger protein synthesis and plasticity.”
According to Schuman, their findings could have implications for
understanding drug addiction and its treatment. “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 said. “This raises the possibility that
some of the signaling that goes awry during addiction may have to do
with local protein synthesis.”
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