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06/21/2004 07:00:00

"Minis" Have Mega Impact in the Brain

Embargoed: Not for Release Until 11:00 a.m. PDT Thursday, 24 June, 2004

PASADENA, Calif. — The brain is a maddeningly complex organ for scientists to understand. No assumption can remain unchallenged, no given taken as a given.

Take "minis" for example. That is, miniature excitatory synaptic events. The location where neurons communicate with each other is the synapse, the tiny gap between the ends of nerve fibers. That's where one nerve cell signals another by secreting special chemicals called neurotransmitters, which jump the gap. The synapse, and its ability to strengthen and wane, is thought to be at the heart of learning and memory. Minis, mere single, tiny packets of neurotransmitters, were always thought to have no biological significance, nothing more than "noise," or background chatter that played no role in the formation of a memory. Minis, it was thought, could be safely ignored.

Maybe not, says Mike Sutton, a postdoctoral scholar in the lab of Erin Schuman, an associate professor of biology at the California Institute of Technology, and an associate investigator for the Howard Hughes Medical Institute. Sutton, Schuman, and colleagues Nicholas Wall and Girish Aakalu report that on the contrary, minis may play an important role in regulating protein synthesis in the brain. Further, their work suggests the brain is a much more sensitive organ than originally perceived, sensitive to the tiniest of chemical signals. Their report appears in the June 25th issue of the journal Science.

Originally, Sutton et. al. weren't looking at minis at all, but at protein synthesis, the process through which cells assemble amino acids into proteins according to the genetic information contained within that cell's DNA. Proteins are the body's workhorses, and are required for the structure, function, and regulation of cells, tissues, and organs. Every protein has a unique function.

A neuron is composed of treelike branches that extend from the cell body. Numerous branches called dendrites contain numerous synapses that receive signals, while another single branch called an axon passes the signal on to another cell.

The original rationale behind the experiment was to examine how changes in synaptic activity regulate protein synthesis in a dendrite, says Sutton. His first experiment was a starting point to ask what happens when we first remove all types of activity from a cell, so he could then add it back later incrementally and observe how this affected protein synthesis in dendrites. "So we were going on the assumption that the spontaneous glutamate release--the minis--would have no impact, but we wanted to formally rule this out," he says.

Using several different drugs, Sutton first blocked any so-called action potentials, an electrical signal in the sending cell that causes the release of the neurotransmitter glutamate. Normally, a cell receives hundreds of signals each second. When action potentials are blocked, it receives only minis that arrive at about one signal each second. Next he blocked both the action potential and the release of any minis. "To our surprise, the presence or absence of minis had a very large impact on protein synthesis in dendrites," he says. It turned out that the minis inhibit protein synthesis, which increased when the minis were blocked. Further, says Sutton, "it appears the changes in synaptic activity that are needed to alter protein synthesis in dendrites are extremely small--a single package of glutamate is sufficient."

Sutton notes that it is widely accepted that synaptic transmission involves the release of glutamate packets. That is, an individual packet (called a vesicle) represents the elemental unit of synaptic communication. "This is known as the 'quantal' nature of synaptic transmission," he says, "and each packet is referred to as a quantum. The study demonstrates, then, the surprising point that protein synthesis in dendrites is extremely sensitive to changes in synaptic activity even when those changes represent a single neurotransmitter quantum.

"Because it's so sensitive," says Sutton, "there is the possibility that minis provide information about the characteristics of a given synapse (for example, is the signal big or small?), and that the postsynaptic or receiving cell might use this information to change the composition of that synapse. And it does this by changing the complement of proteins that are locally synthesized."

The ability to rapidly make more or fewer proteins at a synaptic site allows for quick changes in synaptic strength. Ultimately, he says, this ability may underlie long-term memory storage.

"It's amazing to us that these signals, long regarded by many as synaptic 'noise,' have such a dramatic impact on protein synthesis," says Schuman. "We're excited by the possibility that minis can change the local synaptic landscape. Figuring out the nature of the intracellular 'sensor' for these tiny events is now the big question."