A New Molecular Model of Long-Term Memory

Every list of the Ten or Twelve or even Five Biggest Challenges facing science includes, How and where are long-term memories stored in the brain?

Another theory has just been published, and I pass along Science Daily's summary mainly because it reminded me of the mind-numbing complexity of life at the molecular level. The basic idea is that long-term memories are stories via differing arrangements of "microtubules" in nerve cells. Lattice-like arrangements of the protein Tubulin are a big part of what gives neurons their shape. But might they be doing more?

We know that a big part of how neurons work is "Long Term Potentiation" or LTP, which means that the brief electric flash of a passing nerve impulse leaves the neuron highly sensitive to similar impulses in the future. And we know that a hexagonal enzyme called calcium/calmodulin-dependent protein kinase II (CaMKII) plays a key part in LTP. These molecules change shape in response to nerve impulses. In their changed form, they can add a phosphorus atom ("phosphorylate") some other molecule. In the new model, the addition of phosphorus atoms to Tubulin structures acts like turning and off the transistors in a computer, forming bits and bytes of memory. To quote:

The standard experimental model for neuronal memory is long term potentiation (LTP) in which brief pre-synaptic excitation results in prolonged post-synaptic sensitivity. An essential player in LTP is the hexagonal enzyme calcium/calmodulin-dependent protein kinase II (CaMKII). Upon pre-synaptic excitation, calcium ions entering post-synaptic neurons cause the snowflake-shaped CaMKII to transform, extending sets of 6 leg-like kinase domains above and below a central domain, the activated CaMKII resembling a double-sided insect. Each kinase domain can phosphorylate a substrate, and thus encode one bit of synaptic information. Ordered arrays of bits are termed bytes, and 6 kinase domains on one side of each CaMKII can thus phosphorylate and encode calcium-mediated synaptic inputs as 6-bit bytes. But where is the intra-neuronal substrate for memory encoding by CaMKII phosphorylation? Enter microtubules.

Using molecular modeling, Craddock et al reveal a perfect match among spatial dimensions, geometry and electrostatic binding of the insect-like CaMKII, and hexagonal lattices of tubulin proteins in microtubules. They show how CaMKII kinase domains can collectively bind and phosphorylate 6-bit bytes, resulting in hexagonally-based patterns of phosphorylated tubulins in microtubules. Craddock et al calculate enormous information capacity at low energy cost, demonstrate microtubule-associated protein logic gates, and show how patterns of phosphorylated tubulins in microtubules can control neuronal functions by triggering axonal firings, regulating synapses, and traversing scale.

I find myself very dubious that a bit/byte model derived from electronic computers explains how our brains work, but who knows? Meanwhile, contemplate the dizzying array of structures and processes that make up our cells.