Jim Beran's Talk about Evolution of Posttranslational Modifications (PTMs) and Real-time Plasticity at TSC 2013, Dayalbagh Educational Institute, Agra, India

Description of Content
This incomplete article will include slides Jim Beran showed during his March 4, 2013 talk about evolution of PTMs and real-time plasticity at the TSC 2013 conference held at Dayalbagh Educational Institute (DEI), Agra, India. Next to each slide will be a paraphrase of what Jim said (or intended to say or, in retrospect, wishes he'd said) during his talk. Where relevant, complete citations and other additional information will also be included next to a slide.

Slide 1
My talk today is about evolution of posttranslational modifications or PTMs. PTMs are ancient, going back many millions of years, but I hope to persuade you that more recent evolution of PTMs is relevant to consciousness.

Some of the previous speakers talked faster in order to fit into the reduced time available. At my age, however, it seems better to leave things out. If I've left out so much that you can't understand my points, please let me know and I'll provide more details.

Before I begin, a few words of thanks--

Slide 2


Thanks especially to Dayalbagh Educational Institute and to the organizers for including me in such an interesting session. Also, thanks to Sahil for helping me fix format issues in my slides yesterday afternoon.

But what's this at the bottom about my grandmothers? Without them, I wouldn't be here. But that's not all.

Slide 3
The words "your grandmother" can trigger a distinctive conscious memory of one's grandmother.

Slide 4
Electrical measurements in human brains suggest that certain neurons provide action potentials selectively in response to an image indicating one's grandmother.

The key point here is at the bottom of the slide--if there are grandmother neurons, it's plausible that those neurons initiate conscious experience of one's grandmother.

[The following additional sources discuss neurons that are selective for one person:

Connor, C.E., "Friends and grandmothers", Nature, Vol. 435, 23 June 2005, pp. 1036-1037.

Damasio, A., [CITATION NEEDS COMPLETION]

Quiroga, R.O., Reddy, L., Kreiman, G., Koch, C., and Fried, I., "Invariant visual representation by single neurons in the human brain", Nature, Vol. 435, 23 June 2005, pp. 1102-1107.

The following additional source discusses neuron specificity to faces:

Kreiman, G., Koch, C., and Fried, I., "Imagery neurons in the human brain", Nature, Vol. 408, 16 November 2000, pp. 357-361.

The following additional source discusses face recognition in macaques:

Freiwald, W.A., Tsao, D.Y., and Livingstone, M.S., "A face feature space in the macaque temporal lobe", Nature Neuroscience, Vol. 12, No. 9, September 2009, pp. 1187-1196.]

Slide 5
So this slide compares a grandmother neuron at left with an "everybody neuron" at right, meaning a neuron that provides a signal in response to anyone. The grandmother neuron's signals provide more information, as shown in the graph.

We call the signal from a grandmother neuron a "highly informative" signal, because it indicates a specific person rather than people in general.

And part of our proposal is that changes in conscious experience are initiated by highly informative signals.

Slide 6
Here's a model of how a highly informative signal such as a grandmother signal could change conscious experience. The model includes two neural circuits:  First, an identification circuit provides a highly informative signal, in this case through a grandmother synapse; second, a transducer circuit responds to the grandmother signal, changing to a conscious experience of grandmother. We call this a "neural-to-conscious" or "N-to-C" transducer circuit.

Slide 7
But what is a neural circuit? The latest edition of the Purves et al. textbook titled Neuroscience has a very good explanation.

[For additional information about how "neural circuit" and related terms are used, see the following article:

Usage Examples of "Neural Circuit" and Related Terms]

Slide 8
So where do neural circuits come from? The consensus view in neuroscience is that cytoskeletons of neurons are generically involved in constructing and operating all neural circuits, including those that underlie consciousness.

This image illustrates just a few of the important roles of cytoskeleton in neural circuits--in a growth cone at right, in synapses at upper left, and in transport through axons as shown in the axon at center, and also in transport through dendrites.

But does cytoskeleton do something more, something specific to consciousness? Maybe we can find key features of N-to-C transducer circuits in the cytoskeleton.

Slide 9
One place to look is where the action is--under those highly informative synapses. This image shows a highly informative synapse at right, with neurotransmitter crossing the synaptic cleft to a dendritic spine. Inside the spine are actin filaments in red, and below them, inside the shaft of the dendrite is a microtubule-based structure shown in blue outline. We treat part of the microtubule-based structure as a machine, which we call a "cyto-machine". We propose that coupling of cyto-machines can change conscious experience.

[Complete citation to Woolf et al.:

Woolf, N.J., Priel, A., and Tuszynski, J.A., Nanoneuroscience:  Structural and Functional Roles of the Neuronal Cytoskeleton in Health and Disease, Heidelberg:  Springer, 2009.

The following additional sources also discuss subsynapse cytoskeletal structures:

Jasmin, B.J., Changeux, J.-P., and Cartaud, J., "Compartmentalization of cold-stable and acetylated microtubules in the sybsynaptic domain of chick skeletal muscle fibre", Nature, Vol. 344, 12 April 1990, pp. 673-675.

Svitkina, T., Lin, W.-H., Webb, D.J., Yasuda, R., Wayman, G.A., Van Aelst, L., and Soderling, S.H., "Regulation of the Postsynaptic Cytoskeleton:  Roles in Development, Plasticity, and Disorders, The Journal of Neuroscience, Vol. 30, No. 45, 10 November 2010, pp. 14937-14942.

Woolf, N.J., "Microtubules in the Cerebral Cortex:  Role in Memory and Consciousness", chapter 3 in Tuszynski, J.A., Ed., The Emerging Physics of Consciousness, Berlin:  Springer, 2006, pp. 49-94.]

Slide 10
Not everyone would agree. I received an especially concise challenge from Dayalbagh:  "Microtubules are just protein molecules." (Thanks to Anirudh Kumar Satsangi of Dayalbagh Educational Institute for sending me this challenge.)

Well, microtubules do include protein molecules, predominantly molecules of the protein tubulin. A 10 micron long microtubule, for example, would include more than 30 thousand tubulin molecules, making it quite complex.

If technology cooperates, I'll show two short videos illustrating machine-like behavior of microtubule-based structures.

Slide 11
First a short video of a microtubule approaching an adhesion site on a cell's growth substrate.

[Thank you to Prof. Derek Toomre for permission to present this video. The video may be viewed at this link.]

Slide 12
Second, a short video of a Stentor protozoan feeding with its cilia moving in a coordinated manner.

[Thank you to Prof. Michael W. Davidson for permission to present this video. The video is Video No. 13, viewable at this link.]

Slide 13
And here is a list of machine-like structures based either on microtubules or on a combination of microtubules and actin.

Now let's try to figure out how a cyto-machine might behave.

[Full citations for sources in slide, in alphabetical order by first author's last name:

Adebola, A., and Liem, R.K.H., "Cytoskeletal Interactions in the Neuron", in Squire, L.R., Ed.-in-Chief, Encyclopedia of Neuroscience, Elsevier, 2009, pp. 301-309; pages 307-308 describe growth cone features.

Bush, M.S., Eagles, P.A.M., and Gordon-Weeks, P.R., "The Neuronal Cytoskeleton", in Hesketh, J.E., and Pryme, I.F., The Cytoskeleton:  Cytoskeleton in Specialized Tissues and in Pathological States, Vol. 3, Greenwich, Conn.:  JAI Press, 1996, pp. 185-227; pp. 212-214 discuss assembly of the cytoskeleton in the growth cone.

Fukushima, N., "Microtubules in the Nervous System", chapter 2 in Nixon, R.A., and Yuan, A., Eds., Cytoskeleton of the Nervous System, New York:  Springer, 2011, pp. 55-71; pp. 59-61 discuss neurite outgrowth, including role of microtubules in growth cones.

Purves, D., Augustine, G.J., Fitzpatrick, D., Hall, W.D., LaMantia, A.-S., and White, L.E., Eds., Neuroscience, Fifth Edition, Sunderland, Mass.:   Sinauer Associates, 2012; [BETTER WITH ADDITIONAL DETAILS].

Sleigh, M.A., Protozoa and other protists, London:  Edward Arnold/Hodder & Stoughton, 1989; pp. 29-38 discuss the structure and movement of cilia and flagella.

Tojima, T., and Kamiguchi, H., "The Driving Machinery for Growth Cone Navigation", chapter 19 in Nixon, R.A., and Yuan, A., Eds., Cytoskeleton of the Nervous System, New York:  Springer, 2011, pp. 447-454.

Wastenys, G.O., and Lechner, B., "Microtubules", chapter 14 in Nabi, I.R., Ed., Cellular Domains, Hoboken, N.J.:  Wiley-Blackwell, 2011; [BETTER WITH ADDITIONAL DETAILS].

Westermann, S., and Weber, K., "Post-Translational Modifications Regulate Microtubule Function", Nature Reviews Molecular Cell Biology, Vol. 4, No. 12, December 2003, pp. 938-947; [BETTER WITH ADDITIONAL DETAILS]

]

Slide 14
Just to remind you, a cyto-machine is a microtubule-based structure under a synapse, and the synapse provides a highly informative signal, such as a grandmother signal.

Slide 15
Our first hypothesis is that a cyto-machine provides a machine-like response to a highly informative signal, and the response has an electrical effect. This image shows schematically how a machine-like response could have an electrical effect in a simple circuit.

We also propose that electrical effects in different cyto-machines interact electromagnetically.

Slide 16
Focusing first on the machine-like response, note that I use the term "real-time plasticity" or "RTP" for this type of response.

In short, real-time plasticity occurs in concert with changes in conscious experience, so it could be the basis of N-to-C transduction.

An important point is at the bottom of this slide--as an initial guess, we propose time scales of 20-250 msec for RTP events, which would extend from theta rhythms to gamma rhythms.

[For information about other concepts relating to real-time plasticity, including complete citations to Hameroff (2006) and Woolf et al. (2009), follow this link.]

Slide 17
Turning then to the electrical effects, this image shows how a region might include only a few synapses with cyto-machines, shown as solid red circles; most synapses, shown as open circles, would not have cyto-machines, so that the overall result should still be consistent with other approaches to dendrite analysis, e.g. cable theory.

Slide 18
We propose that teams of coupled cyto-machines compete with each other electromagnetically. When a shift in control occurs between competing teams, the shift affects EEG/MEG waveforms and sometimes changes conscious experience.

Slide 19
This detective is trying to figure out what features of microtubule-based structures might be changing with characteristic times of 20-250 msec.

Last spring at the Tucson conference, Dr. Travis Craddock suggested I look at posttranslational modifications, which turned out to be a brilliant suggestion.

Just to review:

--A PTM modifies a protein after the protein is translated, and most PTMs are catalyzed by enzymes--the enzyme typically operates at a specific amino acid location, attaching or removing a small unit referred to as a "side chain".

--Although several different types of PTMs operate on tubulin, most modify microtubules rather than free tubulin, generally on or near outward extending carboxy terminals (aka C-termini) of microtubules; the third bullet lists several types of tubulin PTMs.

--PTMs are not new--according to one source [Westermann, S., and Weber, K., "Post-Translational Modifications Regulate Microtubule Function", Nature Reviews Molecular Cell Biology, Vol. 4, No. 12, December 2003, pp. 938-947], the known types of tubulin PTMs were present in primitive eukaryotes millions of years ago.

Slide 20
Tubulin PTMs have a number of proposed or proven roles in neurons.

But how could tubulin PTMs relate to cyto-machines?

[Full citations for sources in slide, in alphabetical order by first author's last name:

Brady, S.T., Colman, D.R., and Brophy, P.J., "Subcellular Organization of the Nervous System:  Organelles and Their Functions", chapter 2 in Byrne, J.H., and Roberts, J.L. Eds., From Molecules to Networks:  An Introduction to Cellular and Molecular Neuroscience, 2d Ed., Burlington, Mass.:  Elsevier/Academic Press, 2009, pp. [COMPLETE CITATION; BETTER WITH ADDITIONAL DETAILS].

Craddock, T.J.A., Tuszynski, J.A., and Hameroff, S., "Cytoskeletal Signaling:  Is Memory Encoded in Microtubule Lattices by CaMKII Phosphorylation?", PLoS Computational Biology, Vol. 8, Issue 3, March 2012, pp. 1-16; [BETTER WITH ADDITIONAL DETAILS].

Hameroff, S.R., Craddock, T.J.A., and Tuszynski, J.A., "'Memory Bytes'--Molecular Match For CaMKII Phosphorylation Encoding of Microtubule Lattices", Journal of Integrative Neuroscience, Vol. 9, No. 3, 2010, pp. 253-267; [BETTER WITH ADDITIONAL DETAILS].

Hammond, J.W., Cai, D., and Verhey, K.J., "Tubulin modifications and their cellular functions", Current Opinion in Cell Biology, Vol. 20, 2008, pp. 71-76; [BETTER WITH ADDITIONAL DETAILS].

Janke et al., 2008

Janke et al. 2010

Janke et al., 2011

Purves, D., Augustine, G.J., Fitzpatrick, D., Hall, W.D., LaMantia, A.-S., and White, L.E., Eds., Neuroscience, Fifth Edition, Sunderland, Mass.:   Sinauer Associates, 2012; [BETTER WITH ADDITIONAL DETAILS].

Van Dijk

Wastenys, G.O., and Lechner, B., "Microtubules", chapter 14 in Nabi, I.R., Ed., Cellular Domains, Hoboken, N.J.:  Wiley-Blackwell, 2011; [BETTER WITH ADDITIONAL DETAILS].

Walsh

Wehland, J., "Tubulin Tyrosine Ligase (TTL) and Tubulin Carboxypeptidase (TCP)", in Kreis, T., and Vale, R., Eds., Guidebook to the Cytoskeletal and Motor Proteins, Oxford, UK:  Oxford Univ. Press, 1993, pp. 131-132; [BETTER WITH ADDITIONAL DETAILS]

Westermann, S., and Weber, K., "Post-Translational Modifications Regulate Microtubule Function", Nature Reviews Molecular Cell Biology, Vol. 4, No. 12, December 2003, pp. 938-947; [BETTER WITH ADDITIONAL DETAILS]

Wloga et al. 2010

]

Slide 21
Let's start with a simple hypothesis:  Tubulin PTMs, represented by the green downward arrow, can change microtubules to produce a cyto-machine, shown below the green arrow, changed so that it provides a machine-like response to a synapse signal, suggested by the turned orientation of the "y" part. The machine-like response has an electrical effect, possibly with EM coupling to other cyto-machines, illustrated by the orange arrow at right.

So we have both a machine-like response and an electrical effect.

Slide 22
Remember this image? Why doesn't every synapse have a cyto-machine?

In our hypothesis, only highly informative synapses have cyto-machines. And our hypothesis is based on regulation of posttranslational modifications, also called PTM regulation or sometimes PTMReg. As a synapse provides more informative signals, it provides signals at a reduced rate--for example, the grandmother neuron only provides a signal in response to grandmother, which will occur less often than people in general, signalled by an everybody neuron. We propose that PTM regulation responds locally to this reduced rate, causing PTMs that produce a cyto-machine.

But what is "PTM regulation"?

Slide 23
PTM regulation can, for example, affect where, when, how rapidly, and to what extent PTM occurs.

Why do we care? Well, due to PTM regulation, different combinations of PTMs can occur in different parts of a cell. Specifically, PTM regulation could produce a cyto-machine in one region of a neuron while not producing a cyto-machine in other regions of the same neuron.

Note that these are possible forms of PTM regulation. [ADD CITATIONS HERE OR IN ANOTHER ARTICLE:]

Slide 24
And here are a few more possible forms of PTM regulation.

So the PTM Regulation hypothesis offers a rich palette of possibilities, and, I believe, offers more power to explain evolution of electrical effects in dendrites than cable theory and other non-cytoskeletal approaches. [ADD CITATIONS HERE OR IN ANOTHER ARTICLE:]

Slide 25
This slide illustrates one way PTM regulation might produce cyto-machines selectively, based on two enzymes A and B.

Slide 26
Here is a proposed path for early evolution of PTM regulation, starting with free tubulin without PTM regulation and continuing through the emergence of neurons--a lot of things happened along the way.

And then came polarized neurons--

Slide 27
This part of the proposed evolutionary path focuses on changes in PTM regulation that led to changes in the electromagnetic or EM waveforms detected by EEG and MEG. With further evolution of PTM regulation, shifts between competing teams of cyto-machines arose, so that changing EEG rhythms became possible. Finally, PTM regulation evolved so that a change or shift between competing teams could change conscious experience through real-time plasticity, leading ultimately to humans.

We left out a few details, of course.

In particular, which type of posttranslational modification first produced a cyto-machine? Regulation of that type of PTM might account for all the advances shown here.

Slide 28
This slide first compares two overall groups of PTMs--monomodifications with a signel unit side chain and polymodifications that can produce side chains with more than one unit. We suggest that polymodifications are the more likely candidate to produce cyto-machines.

Slide 29
This slide then compares two types of polymodifications of tubulin--polyglutamylation and polyglycylation. We suggest that polyglutamylation is the more likely candidate for the reasons shown here. Note that extensive polyglutamylation has been found in neurons, but polyglycylation has not.

Slide 30
A cyto-machine produced by polyglutamylation might follow a cycle as shown here. Polyglutamylated C-termini tails would be ordered as shown at left, preventing ion flow along a microtubule. In response to a synapse signal or EM coupling, a release phase occurs, causing the tails to be disordered as shown at right, and allowing ions to flow, producing a transient electrical current. Then, during a recovery phase, the tails are again ordered and ions accumulate until the next release phase.

Slides 31-35
These slides (which I didn't have time to discuss) explain how transient electrical currents might be amplified in a cascading manner, leading to N-to-C transduction.











Slide 36
So here at last is our finished cyto-machine. And the conclusions:  Microtubules are more than just protein molecules, and dendritic cytoskeleton has features specific to consciousness.

Slide 37
Thanks for your attention!

Slide 38
And here is how you will be able to get more information.