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Technique Begins To Decode Spiny Signaling in Brain
In experiments with rat brains, researchers have found that the nerve cells crucial for voluntary movement react differently to the same chemical message depending on whether the cells are resting or actively sending messages to other neurons.
Using a novel dual-laser scanning microscope, Adam Carter (right) and Bernardo Sabatini captured unprecedented closeups of calcium signaling in the dendrites of neurons important in normal movement and in Parkinson's and Huntington's diseases. (Photo by Graham Ramsay)
The detailed findings come from a new two-laser scanning microscope that provides unprecedented closeups of the main type of nerve cell in the striatum. In fact, postdoctoral fellow Adam Carter and Bernardo Sabatini, HMS assistant professor of neurobiology, were able to zoom into the thicket of branching dendrites to the tiny synapses that receive the electrical signals jumping from neuron to neuron in the brain.
Their paper, published in the Oct. 28 Neuron, showcases a powerful new tool with the potential to help scientists understand how the neurons process thousands of signals from other nerve cells and what may go wrong in diseases such as Parkinson's and Huntington's.
"Much work remains to be done before we fully understand the implications of these findings for medium spiny neuron function and pathology, but Carter and Sabatini have given us our first direct look into dendritic processes that are likely to be at the core of many disabling basal ganglia diseases," wrote James Surmeier and Nelson Spruston of Northwestern University in an accompanying commentary.
Tracing Circuits
In people, the circuitry from the striatum to the basal ganglia somehow helps turn thoughts into actions that grow more fine-tuned with practice, such as grasping a cup and guiding it to our mouth when we want a sip of coffee. The medium spiny neurons that make up most of the striatum have been intensely studied for their role in some movement disorders. In Huntington's disease, these cells deteriorate and die, resulting in uncontrolled movements more likely to knock over that cup of coffee. People with Parkinson's disease, on the other hand, lose the dopamine-producing cells that modulate incoming messages to the striatum, making it difficult to initiate the correct movements to pick up the coffee cup.Until now, studies of the medium spiny neurons have been limited to recordings of the bulbous cell body, which is just big enough for a researcher's electrode. But the electrical activity in these neurons begins upstream in the dendrites and spines as a cacophony of thousands of inbound local signals that mix and change in milliseconds.
"The problem with medium spiny neurons is that they are not really 'medium'--they're tiny," write Surmeier and Spruston. The dendrites "are too fine to yield to patch-clamp techniques that have told us so much about the dendritic function in other parts of the brain. To make matters worse, their dendrites are densely studded with spines that harbor the all-important glutamatergic synapses," the connections that activate a nerve cell.
Two-laser Technique
To discover the details of the activity along the dendrites, Carter and Sabatini combined 2-photon laser uncaging of glutamate with 2-photon laser scanning microscopy. In the lab, the sensitive lasers rest on a one-ton table with built-in shock absorbers to dampen the vibrations of nearby construction, footsteps in the hallway, and even loud voices.
| "Much work remains to be done before we fully understand the implications of these findings for medium spiny neuron function and pathology, but Carter and Sabatini have given us our first direct look into dendritic processes that are likely to be at the core of many disabling basal ganglia diseases." |
Meanwhile, the nerve cell has been filled with a chemical dye that glows in response to the calcium influx. The second laser illuminates the dendrite and spine and allows measurements of the rapid rise and fall of calcium.
The nuances of calcium signaling partly depend upon its route of entry. "The different calcium sources couple to different downstream signaling pathways and are likely to influence synaptic plasticity and gene expression in these neurons," Carter said.
By systematically blocking various calcium channels, the researchers found that glutamate selectively triggered one type of receptor in the synapses of resting neurons, which opens briefly and allows only a little calcium to pass through. In active cells, on the other hand, glutamate preferentially triggered another type of receptor, which stays open longer and allows more calcium inside. Voltage-sensitive calcium channels also responded to the up and down states of the neuron, with one type open in active neurons and another type open in resting cells.
"These state transitions, thought of as turning on the output of the cell, really have large effects on how the cell responds to signals from other cells," Sabatini said.
This new technique allows scientists to address the question of what the intermediate steps are in the generation of a nerve cell impulse from its origin at the individual synapse. It is going to make a big difference in understanding the synaptic integration in the dendrite that leads to the nerve cell's output, said Charles Wilson, a neurophysiologist at the University of Texas at San Antonio. "It's not the answer to the question, but it's proof that we will be able to answer this question soon."
--Carol Cruzan Morton