Perhaps you really can't teach an old neuron new tricks.

"The plasticity [changeability] of the nervous system is known to decrease with advancing age," averred developmental neurobiologist Jeff Lichtman at Washington University School of Medicine in St. Louis. "What is the underlying cause for this loss of neuronal flexibility?" he asked rhetorically, and suggests an answer in the August 2003 issue of Nature Neuroscience.

Lichtman is senior author of the relevant article in that issue titled "Synaptic dynamism measured over minutes to months: Age-dependent decline in an autonomic ganglion."

"I think our principal finding," he observed, "is that once animals reach maturity, synaptic connections in this part of the nervous system stabilize. Meaning that they don't disappear, they're not being replaced, they're not undergoing a kind of turnover. The underlying question of this work," Lichtman continued, "is that animals, like human beings, are unusual. Mammals in general have this property, that most of the tissues in the body turn over, but neurons are to a great extent immovable.

"That is," Lichtman continued, "many of the neurons that undergo their last mitosis before birth are therefore born in the cells before the animal reaches birth - gets outside the womb. Those cells are with us until they die. That's not the same of skin and blood cells, which have constant turnover. So although the cells last a lifetime, that stability permits their interconnections at the synapses. There they talk to each other with a kind of turnover like other tissues. This turnover is plasticity of synaptic connections, which sometimes disappear. They could underlie animals, especially mammals that can learn things and remember them for long periods of time. Perhaps this is due to some changes in connectivity in the nervous system - synapses being formed.

"The ultimate question," he went on, "concerns the cell biology of the cell synapse: How long does it live? Stay in one place at one time? The only previous work that directly addressed this question of how nerve terminals of the synapses that come off of nerve cells was done at the neuromuscular junction."

From Birth Through 80s And Older

"The finding we encountered there that was a bit surprising," Lichtman said. "Namely, that after animals got out of the developmental period, where there's a lot of rearrangements going on, neuromuscular junctions were unchanged for the vast majority of a mouse's life. When an animal gets to be very old, it breaks down. But over middle age it's very stable. Of course that's the neuromuscular junction, the connection between nerve and muscle. It's deemed a stupid' part of the body. There's no reason that it should be undergoing change, but if you look at synapses where the target is not a fiber but a nerve cell, then you'd find a lot more plasticity. We can see these synapses over time very easily - just watching the mice, which we did. To our surprise they turned out to be stable.

"And that suggested an interesting corollary of learning and memory and plasticity. Not only did we have to have a way of modifying the nervous system to learn something, but also to have some way of stabilizing that change so it would last a long time. In this part of the nervous system we looked at the mandibular ganglion. It stayed there for a very long period of time.

"So now we looked at an autonomic ganglion and found stability. This is not the brain. It's part of the nervous system we looked at, in particular, because of the advantageous peripheral nature of the synapses. They were accessible over time to animals where they are related to a salivary gland in the neck. That cluster of nerves does not reside in the CNS, but in the periphery, which gives us good optical access to them - so that's why we used it.

"Dendritic spines, the target side of the synapses, the terminal that touches a neuron, those spines don't change very much for long periods of time. Again suggesting that from a distance there might be some implications for stability of synapses in the CNS.

"Our in vivo experiments with old and young mice," Lichtman volunteered, "were not experiments in the traditional sense of modifying parameters and then asking what the outcome was. Our aim here was to follow the advice of Yogi Berra, the famous Yankee, who said, You can observe a lot by just watching.' And that's all we did; we just looked. We tried hard not to interfere with normal processes, so we used light imaging techniques where we didn't consume a lot of light, because light itself is toxic. It might cause changes that would be due to us, rather than by biology's normal actions."

Designer Mice Pose For 3-D Microscopy

"Our co-authors designed mice in collaboration with my own lab, in which the nerve cells are just filled with fluorescent proteins from jellyfish. In these mice, under anesthetic, the ganglion's innervation was prestained," Lichtman said.

"We exposed the ganglion in a living animal, unmoving, while we took 3-D pictures under confocal microscopy. We sewed up the wound, allowed the mouse to recover from anesthesia, which took about 15 to 20 minutes. Then the animal went its merry way until the next imaging session. We got time-lapse images in a living animal, as opposed to fixed material from different aged mice. We could never infer if synapses were stable or not if we didn't look at the same cell over time. Some of the cells we looked at for close to two years - 508 days - were the longest order of magnitude any nerve cell in a living animal has ever been studied.

"In this paper," Lichtman noted, "we restricted ourselves to animals that are young or going through middle age, and not getting into the very advanced-aged period of time when things change dramatically. We're presently working on a paper about aging per se. When animals get very old, mammals in particular, they begin to show changes in their behavior that could be accounted for by modifications in the way synapses are connected. We're very interested in that," he concluded.

No Comments