ComBio: Memories are made of this

It seems that memories are made of... cadherins.

While cadherins -- cell adhesion molecules -- do not actually store memories, at the very least they have a major role in organising the basic architecture of the brain, and the dense filigree of fine neural interconnections in which memories are mysteriously stored.

In his plenary lecture at ComBio 2003, Prof Masatoshi Takeichi, the discoverer of cadherins, described how several of the 100-odd members of the cadherin family work.

Complementary cadherins projecting from adjacent cell membranes "shake hands" to bridge the space between the cells. They bind cells into functional communities -- including brain cells.

Takeichi and his co-workers at the RIKEN Centre for Developmental Biology in Kobe, Japan, have shown that cadherins team up to form and stabilise synaptic connections between individual neurons in the brain -- they are critical to the formation of the brain's myriad neural networks.

Biology textbooks have classically depicted synapses -- the junctions between communicating nerves -- as having narrow gaps, across which the neurotransmitters that carry signals between nerves diffuse. Like Michelangelo's Sistine Chapel painting of God extending a finger to imbue Adam with life, networked nerves supposedly made no physical contact.

But Takeichi's team has shown they do. Cadherin bridges actually surround the neurotransmitter zone, locking the mushroom-like knobs at the ends of projecting dendrites to the axon of the target neuron, or to spines along the body of the axon.

New connections form when new memories are being laid down, and are reinforced by repeated access, a process called long-term potentiation (LTP)

Cadherins have an active role in forming synapses. Takeichi's team has demonstrated their function in a knockout mouse for alpha-N cadherin, In the mouse's brain, the thread-like filipodia that give rise to dendrites grow towards nearby neurons, but fail to make stable connections -- and keep on growing.

In knock-in mice over-expressing alpha-N cadherin, the projecting dendrite locks onto the axon so tightly that it pulls its shaft out of shape. It cannot disengage, so the synaptic connections can no longer be remodeled.

Takeichi's team has produced another mouse knockout for cadherin-11, with intriguing results.

The mouse has a much shorter face and nose than its normal littermates. Takeichi describes its appearance as "koala-like". Neurons in its hippocampus, the brain compartment that regulates memory, appear to more easily change into LTP mode, suggesting the mouse may have a better long-term memory. It is more efficient at running mazes, and behaves more calmly in anxiety experiments.

Humans have shorter, more vertical faces faces than their chimp and gorilla cousins, and a superior memory. But Takeichi says his team has no data on possible cadherin-based differences in neuronal architecture and wiring between humans and apes -- human brains are not easily accessible for study.

However, his team plans eventually to explore the possible role of cadherin mutations in brain abnormalities and mental disorders in humans.