Long-Term Potentiation Equals Spinal Growth

For this article, Leslie Pray interviewed Tobias Bonhoeffer, managing director, chairman of the board, and cellular and systems neurobiology department head at the Max Planck Institute of Neurobiology in Munchen-Martinsried, Germany. Data from the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. F. Engert, T. Bonhoeffer, "Dendritic spine changes associated with hippocampal long-term synaptic plasticity," Nature, 399:66-70, May 1999. (Cited in 162 papers) Memory, despite some advances, remains a neurological mystery. While scientists know that people "store memories in the brain either by changing the strength of the synapse or by producing new synapses," says Tobias Bonhoeffer, cellular and systems neurobiology department head at the Max Planck Institute of Neurobiology in Munchen-Martinsried, Germany, synapses can weaken over time. With this Hot Paper, Bonhoeffer and co-author Florian Engert showed how new spinal growth occurs in the hippocampal region during memory formation. Neuroscientists have long speculated that information storage would likely be more permanent if changes in synaptic strength were accompanied by some sort of morphological alteration in the brain, in particular among the tiny dendritic protrusions known as spines.1 These specialized structures on the neuron's postsynaptic end are 1 to 2 µm long, and tens of thousands of spines can coat a single neuron, making "the whole dendrite look spiny, like a rose," says Bonhoeffer. The curious thing about spines isn't simply their large number, rather the observation that "the vast majority of synapses sit on the head of a spine," says Bonhoeffer. In fact, the spine-synapse relationship is nearly one to one, he notes, which partially explains why scientists believe that the spines have something to do with memory: the more spines, the more synapses, and therefore, goes the theory, a better memory. But scientists have had a difficult time detecting whether changes in spinal morphology are associated with those synaptic changes that occur when information is being stored.1 Only recently have novel time-lapse imaging techniques made it possible to visualize these changes. Miming, Storing and Proving Bonhoeffer and Engert, now an assistant professor at Harvard Medical School, used a time-lapse imaging technique known as two-photon microscopy to observe spines in the CA1 region of the hippocampus after the synapses had been stimulated in a way that "mimics what happens in the brain when you store information," explains Bonhoeffer. That stimulation is known as long-term potentiation, or LTP. They also used another novel technique, local microsuperfusion, which enables researchers to focus on a very small, specific area of the neuron to more readily detect new spinal growth. The investigators showed that LTP is accompanied by new spinal growth. In control regions where LTP had been blocked, no significant spinal growth occurred. Thus, by using new techniques, the researchers found "the morphological correlate of the storage of information in the brain," says Bonhoeffer. However, "like always in biological science, there is never complete proof that something is true," Bonhoeffer says. From what he and Engert saw, "it seemed extremely likely that new spines correlate with strengthening of synapses." But because they couldn't completely exclude the possibility that what they saw were artifacts of their methods, it was reassuring when two other groups of researchers showed the same effect, says Bonhoeffer.2,3 Researchers from the Cold Spring Harbor Laboratory in New York also used time-lapse two-photon imaging to show that spinal growth is "associated with stimuli that induce long term potentiation," says neuroscientist Karel Svoboda, Howard Hughes Medical Institute investigator at Cold Spring and the paper's senior author.2 "Our study was very similar in spirit to the Engert and Bonhoeffer paper." A third group used electron microscopy instead of two-photon imaging.3 This study, which appeared in Nature a few months later, represents a "completely different way of looking at the same question and coming to the same conclusion," Bonhoeffer says. In fact, it was "the three papers together that made the whole thing a solid case," he says. Svoboda's group continues to look at the mechanisms of morphogenesis in vitro and to relate spine growth to changes in behavior in vivo. In a follow-up study, he and his colleagues showed how sensory experience can lead to changes in spine structure.4 For Bonhoeffer, the question is, "What is the functional role of these new spines?" Since every spine contains a synapse, the appearance of more spines should mean more synapses. But the evidence is murky, so "the most important and most relevant next step is to make sure that those new spines that we observed do really contain synapses." Leslie Pray (lpray@nasw.org) is a freelance writer in Leverett, Mass. References 1. R. Yuste et al., "Morphological changes in dendritic spines associated with long-term synaptic plasticity," Annual Review of Neuroscience, 24:1071-89, 2001. 2. M. Maletic-Savatic et al., "Rapid dendritic morphogenesis in CA1 hippocampal dendrites induced by synaptic activity," Science, 283:1923-7, 1999 (cited in 168 papers). 3. N. Toni et al., "LTP promotes formation of multiple spine synapses between a single axon terminal and a dendrite," Nature, 402:421-5, 1999 (cited in 95 papers). 4. B. Lendvai et al., "Experience-dependent plasticity of dendritic spines in the developing rat barrel cortex in vivo," Nature, 404:876-81, 2000.

Long-Term Potentiation Equals Spinal Growth

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