Despite
a century of research, memory storage in the brain has remained
mysterious. Evidence points to synaptic connection strengths among brain
neurons, but synaptic components are short-lived and yet memories can
last lifetimes. This suggests synaptic information is encoded and
hard-wired at a deeper, finer-grained molecular scale.
In a paper in the March 8 issue of the PLoS Computational Biology, University of Arizona anesthesiologist Stuart Hameroff, MD,
and physicists Travis Craddock and Jack Tuszynski of the University of
Alberta demonstrate a plausible mechanism for encoding synaptic memory
in microtubules, major components of the structural cytoskeleton within
neurons.
Microtubules are cylindrical hexagonal lattice polymers of the protein
tubulin, comprising 15% of total brain protein. Microtubules
define neuronal architecture, regulate synapses, and are suggested to
process information via interactive bit-like states of tubulin. But any
semblance of a common code connecting microtubules to synaptic activity
has been missing. Until now.
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 (Figure). They calculate
enormous information capacity at low energy cost, and show how patterns
of phosphorylated tubulins in microtubules can not only store memory,
but control neuronal functions by triggering axonal firings, regulating
synapses, and traversing scale.
Microtubules
and CaMKII are ubiquitous in eukaryotic biology, extremely rich in
brain neurons, and capable of connecting membrane and cytoskeletal
levels of information processing. Decoding and stimulating microtubules
could enable therapeutic intervention in a host of pathological
processes, for example Alzheimer’s disease in which microtubule
disruption plays a key role, and brain injury in which microtubule
activities can repair neurons and synapses.
Dr.
Hameroff, senior author on the study, said: “Many neuroscience papers
conclude by claiming their findings may help understand how the brain
works, and treat Alzheimer’s, brain injury and various neurological and
psychiatric disorders. This study may actually do that.”
