The brain’s molecular memory code revealed?

CaMKII activated by synaptic calcium influx extends 6 kinase domains above

and below a central domain. The insect-like CaMKII binds to a microtubule,

its 6 kinase domains precisely matching, binding to, and collectively

phosphorylating 6 tubulins in the hexagonal lattice. CaMKII departs,

leaving a memory trace which evolves and computes in the microtubule

lattice. (Craddock et al, PLoS Computational Biology, in press)

Memory depends on variable synaptic connection strengths among brain

neurons, channeling activity through specific network pathways. But synaptic

components are short-lived and frequently re-cycled, and yet memories

can last lifetimes, suggesting encoding of synaptic information and memory

at a deeper, finer-grained molecular scale, something akin to the genetic code

in DNA. In a paper to appear in the journal PLoS Computational Biology,

physicists Travis Craddock and Jack Tuszynski of the University of Alberta,

and anesthesiologist Stuart Hameroff of the University of Arizona put forth a

plausible mechanism for encoding synaptic memory in microtubules, major

components of the cytoskeleton within neurons.

Microtubules govern neuronal growth, regulate synapses and are composed

of ‘tubulin’ proteins which self-assemble into cylindrical hexagonal lattices.

Generally considered as merely bone-like structural girders, microtubule lattices

have also been proposed to process information via dynamic interactive states

of tubulins. But any semblance of a common code connecting synaptic activity

to microtubule processes has been missing. Until now.

The best experimental model for neuronal memory.is long term potentiation

(LTP) in which intense, 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 each CaMKII can thus phosphorylate and encode calcium-mediated

synaptic inputs as 6-bit information bytes. But where is the intra-neuronal substrate

for memory encoding by CaMKII phosphorylation? Enter microtubules.

Using molecular modeling, Craddock et al show a precise match between the spatial

dimensions, geometry and electrostatics 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 information bytes, resulting in hexagonally-based

patterns of phosphorylated tubulins in microtubules. They calculate enormous information

capacity at extremely low energy cost, and provide mechanisms by which patterns of

phosphorylated tubulins in microtubules can influence axonal firings, regulate synapses, and

traverse scale.

Microtubules and CaMKII are ubiquitous in eukaryotic biology, and apparently able

to function as solid state information processors organizing real-time cellular functions,

complementing the more static genetic information in DNA. Decoding microtubule

bits and bytes could enable therapeutic intervention in a host of pathological processes,

for example Alzheimers disease in which microtubule disruption plays a key role, and

brain injury in which microtubule activities can repair neurons and synapses.

Hameroff, senior author on the study, said: “Many neuroscience papers conclude by

claiming their findings may help understand how the brain works, and treat Alzheimers,

brain injury and various neurological and psychiatric disorders. This study may actually

do that.”

PLoS Computational Biology (in press)

Cytoskeletal signaling: Is memory encoded in microtubule lattices by CaMKII phosphorylation?  

Travis J. A. Craddock¹, Jack A. Tuszynski^{1, 2}, and Stuart Hameroff³

¹Department of Physics, University of Alberta, Edmonton, AB, Canada

²Departments of Oncology, Cross Cancer Institute, Edmonton, AB, Canada

³Departments of Anesthesiology and Psychology, Center for Consciousness Studies,

University of Arizona, Tucson, AZ, USA