Johns Hopkins University researchers say they have used mouse mutants to define critical steps involved in learning basic motor skills.

The study focused on the behavior of two proteins and the specific steps they take to control a neuron’s ability to learn by adapting to signals from other nerve cells.

The researchers say their study pulls together a growing body of evidence from the field and shows definitively that interactions between the PICK1 protein and another group of proteins known as AMPA receptors are critical for specific neurons in the lower back part of the brain to become de-sensitized to certain molecular signals.

The findings are detailed in the March 16 issue of the journal Neuron.

Researchers at the Max Planck Institute of Neurobiology, Munich/Germany have discovered that long-term potentiation (a strengthening of synaptic connections that is thought to be the cellular basis for learning and memory) in a hippocampal neuron goes along with morphological changes in specialized microscopic structures, the so-called dendritic spines (Nature, May-6th, 1999). Most neurobiologists believe that memories are encoded in the changing strength of synaptic connections in the brain, that is, in the effectiveness with which one neuron in the brain communicates with another. As the human cerebral cortex contains about 1014 (100 trillion) synapses, a lot of information could be stored.

Understanding how memory works is one of the fundamental problems in neurobiology. Naturally, then, many neurobiologists are concerned with how synaptic strengths are regulated to store information. One problem in particular has been to answer the question whether the functional changes in the strength of synaptic transmission are also correlated with structural changes in neurons as this could "engrave" the information in the brain in a more durable and permanent way than a mere physiological change. An especially attractive candidate for such structural changes is the postsynaptic spine, a tiny protrusion of the dendritic tree that is distinguished by several features: it is the almost exclusive carrier of the postsynaptic sites of excitatory synapses, it covers a neuron in numbers far greater than a thousand and it has so far managed to dodge the efforts of neuroscience to elucidate its function quite effectively.

Florian Engert and Tobias Bonhoeffer at the Max Planck Institute of Neurobiology in Munich have now shown that indeed — as has long been speculated — spines do change their morphology when synapses are functionally strengthened.

This advance has been possible through the combination of two new techniques, two-photon laser scanning microscopy (TPLSM) and local micro-superfusion. TPLSM is a novel way of very efficiently visualising microscopic objects that have been stained with a fluorescent dye. One of its great advantages is that it minimizes damage to the cell and it has thus for the first time made it possible to observe single cells in living tissue for extended periods of time with high spatial resolution. Earlier studies had also already looked for changes in spine morphology, but it was the literal search for the needle in the haystack since the researchers did not precisely know where the spine changes would occur. The micro-superfusion technique then was crucial to overcome this problem. It allowed to reduce synaptic transmission and therefore the potential site of morphological changes to an area of no more than 30 µm in diameter. To do this Engert and Bonhoeffer used a trick. They blocked synaptic activity in the whole slice by bathing it in an inhibitory agent and used superfusion with "normal" solution to remove the inhibitor in the small area only (see Figure). This restricted synaptic activity and thus the site of activity-dependent plasticity to a very small region which could then readily be scrutinized for structural changes with the TPLS-Microscope before, during and for an extended period after the induction of synaptic plasticity.

Using this arrangement Engert and Bonhoeffer could show that after the induction of long-lasting (but not short-lasting) functional enhancement of synapses new spines appeared on the postsynaptic dendrite, while in control regions on the same dendrite or in slices in which functional changes had been prevented pharmacologically no significant spine growth occurred.

In summary the experiments show that the induction of functional synaptic changes goes along with the emergence of new spines. The most attractive explanation for this phenomenon is the formation of new synapses that appear within an hour after the initiating stimulus. Although more experiments on the precise nature of these changes are necessary, the data provide strong evidence that not only physiological but also structural changes play an important role when neurons change the efficacy of their connections.