Synapse Proteomics

Lily Tomlin, in her comedic role as Trudy the bag lady, in the 1991 film Searching for Signs of Intelligent Life in the Universe, mentioned that she thought she likely suffered from a few "lapses in the synapses."

In all seriousness though, both Deric at Mindblog and Mo at Neurophilosophy have referred recently to work being done on synaptic complexity.

1. Deric's post, Increasing complexity of nerve synapses during evolution refers to this Nicholas Wade article in the New York Times, Brain Power May Lie in Complexity of Synapses, which looks at the possibility that the more complex the synapses are, the more brain power there is likely to be.
(Image from the Nicholas Wade NYT article, originally from the journal Nature Neuroscience.)
The NYT article looks at this paper, Evolutionary Expansion and anatomical specialization of synapse proteome complexity by Emes RD, Grant S, et al.

2. Meanwhile, Mo at Neurophilosophy wrote this blogpost: Synapse proteomics & Brain Evolution about the same paper.
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In the first part of a series of posts here called Nervous System Basics (see Part I), I wanted to draw attention to the fact that there are 100 billion neurons, 1-10 trillion glial cells, and 100 trillion chemical synapses.

This is just so hard to imagine (i.e., form a mental construct about). And those are just the numbers associated with the complexity due to numbers of microscopic-sized physical structures. Now add large numbers of complexities in the synapses themselves, at a molecular (beyond ordinary microscopic-sized) order of magnitude, and you might catch a glimpse of how complex our brains truly are.


HERE ARE SOME TAKE HOME POINTS

1. It's not just about brain size or numbers of neurons:
From the Wade NYT piece:

"A human brain... is three times the volume of a chimpanzee’s... (however) in fact the synapses get considerably more complex going up the evolutionary scale, Dr. Grant and colleagues reported online Sunday in Nature Neuroscience. In worms and flies, the synapses mediate simple forms of learning, but in higher animals they are built from a much richer array of protein components and conduct complex learning and pattern recognition..."

(From Mo's Neurophilosophy post:)

"a new study which used bioinformatics to compare the synapses of distantly related species suggests that size may not be the most important factor in human brain evolution after all. Instead, the new findings, which were published online in Nature Neuroscience on Sunday, suggest that it is an increase in the complexity and number of synapses that was crucial for the emergence of complex behaviours and cognition."

2. Each synapse has a role in adding complexity and therefore brainpower:

"If the synapses are thought of as the chips in a computer, then brainpower is shaped by the sophistication of each chip, as well as by their numbers. “From the evolutionary perspective, the big brains of vertebrates not only have more synapses and neurons, but each of these synapses is more powerful.." (- Wade quoting Dr.Grant)

(From Mo's post:)

"On the receiving end of the synapses of mammals, immediately beneath the membrane, there is a dense network of proteins called the postsynaptic density (PSD). The PSD contains more than 1,000 proteins, which can broadly be divided into 3 different classes: the components of around 12 parallel but converging signaling pathways.."

3. Synapses preceded nervous systems: (Wade again:)

"He included yeast cells in his cross-species survey and found that they contain many proteins equivalent to those in human synapses, even though yeast is a single-celled microbe with no nervous system. The yeast proteins, used for sensing changes in the environment, suggest that the origin of the nervous system, or at least of synapses, began in this way."

4. Synaptic problems ("lapses in the synapses") may be responsible for mental disorders (Wade again:)

"The roots of several mental disorders lie in defects in the synaptic proteins, more than 50 of which have been linked to diseases like schizophrenia, Dr. Grant said."

5. Synapses might "evolve" by 'tweaking' themselves? :

In Mo's post, there is a link to this page, on postsynaptic density or PSD. In it is stated the definition; "The postsynaptic density is a multiprotein complex containing membrane proteins, signaling molecules and core PSD proteins." Mo says,

"The PSD contains more than 1,000 proteins, which can broadly be divided into 3 different classes: the components of around 12 parallel but converging signaling pathways, with the components of each one clustered to form an enormous macromolecular complex; the cytoskeletal and scaffolding proteins which tether the complexes to precise locations at the membrane, in close proximity to the receptors which activate them; and the enzymes which regulate the movements and functions of the complexes and their individual components within the membrane.

The regulatory enzymes act by making minor modifications in the structure of the signaling pathway components. One apparently ubiquitous form of modification involves the addition of a small molecule called a phosphate group to a specific site on the target protein. This process, phosphorylation, is catalyzed by enzymes called a kinases. It is reversible, and acts like a switch - the phosphate groups can be removed by another group of enzymes called phosphatases, and the addition or removal of a phosphate group activates or inhibits a target protein.

These signaling pathways are incredibly complex - the enzymes all act on multiple targets, and differ in their effects on each. Furthermore, they are subject to the same regulatory mechanisms as the proteins they regulate. They too can have phosphate groups or other small molecules added or removed, and in some cases, activate or inhibit themselves by catalyzing modifications of their own structure."

(This is really clear, and I'd like to thank you Mo, for being such a good writer on such a difficult topic that even a regular person like me can catch a glimpse of some immense implications...)

6. Proteomics (i.e., the study of proteins) might help researchers unravel synaptic mysteries and reveal more about how the brain "works": (Mo again:)

"The interactions between these signaling pathways are very poorly understood, largely because researchers were until recently only able to investigate one or two of the components at any one time. This is where proteomics comes into its own, because it allows for simultaneous analysis of hundreds or thousands of molecules, enabling researchers to begin teasing apart the pathways and networks instead of plucking individual components out one at a time."

Additional Links/Reading:
1. Genes to Cognition program headed by Seth Grant
2. Grant S; Organization of brain complexity - synapse proteome form and function (2006, open access)
3. Genes2Cognition
4. Grant S; The synapse proteome and phosphoproteome: a new paradigm for synapse biology (2006, 5-page pdf)
5. Hensch TK, Fagiolini M; Excitatory-Inhibitory Balance: Synapses, Circuits, Systems (2003): Chapter 1, The Organization and Integrative Function of the Post-Synaptic Proteome, is by Grant S et al.
6. Ziff EB; Getting to synaptic complexes through systems biology (2006)
7. Short (5 minute) YouTube video: Neurons and Neuro-transmitters
8. Press release June 2009, from the Sanger Institute where Seth Grant works: Origins of the Brain: Complex Synapses drove brain evolution
9. Emes R and Grant SG et al; Evolutionary expansion and anatomical specialization of synapse proteome complexity, Nature Neuroscience, June 2008, open access 8-page pdf

Nervous System Basics VII: UNIFORMITY WITH VERSATILITY

Here is Angevine's 6th attribute:

"Uniformity with Versatility
The vertebrate nervous system is accurately and reproducibly assembled. In animals of like genus and species it appears almost identical, although this is not absolute when genetic histories differ. Minor variations in the size of components and arrangements of cells are seen between species, striking ones between classes, orders and families. Yet basic regions and properties, cells and circuits, and overall organization are sufficiently alike to permit instant recognition off the basic brain plan and insights as to what these parts and cells contribute to function. Humans show increases in brain size and regional elaboration, numbers of neurons and prominence of certain connections, variations in cerebral sulcation, hemispheric asymmetry, and long projections."

Once nature came up with a way to do something at a cellular level and this cellular model survived all the predatory and thermodynamic slings and arrows, it became handed down more less intact. Neurons are highly useful, but expensive metabolically; once a working model became established it became highly conserved, replicated endlessly in all manner of species filling all manner of niches, each species phenotype using the basic neuron model in endlessly inventive ways.

As creatures evolved, bits got added to the nervous system, but nothing was ever really deleted from it. As a result, we share basic neuron structure design with animals that date back to the days prior to the division that occurred between vertebrates and our invertebrate cousins on the planet - everything considered "animal" has neurons, except for sponges. The list includes radially symmetric jelly fish, starfish, etc., insects... - all have neurons (i.e., we humans are not "special" for having neurons, but our neuron number and arrangement is - "specie-al" to humans).

As evolution proceeded our (really ancient animal) ancestors found their neuronally equipped selves becoming bilaterally symmetrical, better for getting a grip on the world to haul a little body physically perhaps, but requiring more hard drive to coordinate two sides. So the nervous system found itself clumped up a bit at one end. After that it was probably just more economical for special senses to evolve where there was already extra hard drive built in.

Everything after that, all the way to us, is a result of addition rather than truly different body plan. Apparently no other types of body plan were able to make it in the real world of predation and thermodynamic forces. So we share our bilaterally symmetric body plan with all other primates, quadrupeds, land vertebrates, and sea vertebrates including fish, who "invented" backbones and spinal cords, and everything else all the way back through time to whatever represents the fork in the road that led to worms on one side and fish ancestors on the other. Although worms lack a vertebral arrangement or any bones for that matter, they do have a bilaterally symmetric body plan, neurons, and a little "brain", up in front, to run all of it.

Additional reading:
1. Principles of Brain Evolution, Georg F. Streidter
2. Brain Architecture: Understanding the Basic Plan, Larry W. Swanson
3. Development of the Nervous System, Sanes, Reh and Harris