Older people want to be able to remember like they used to and, for sure, everybody wants to be smarter than they used to be. But so far, all attempts to enhance intelligence and memory—these two functions together are called cognition—have not been too impressive. The use of “mental exercises” in the form of crossword puzzles, sudoku, chess playing, etc. have not withstood the scrutiny of rigorous experiments. Some drugs that target early Alzheimer’s disease may slow down the progression of memory loss in some patients, but only marginally.

 

Enter CNF1

Cytotoxic Necrotizing Factor 1, or CNF 1, is a neurotoxin secreted by E.coli, a common bacteria that colonizes human and almost all other animals’ guts. When this neurotoxic protein is injected into brains of mice, surprise, surprise, they learn better and remember longer. Sounds too good to be true? But, it isn’t!

 

Neuronal structure

Neurons are made up of cell bodies that can be elongated, egg-shaped, or some other defined or ill-defined shapes. The important thing about them is that from the body, they radiate out narrow, long branches called dendrites, and from each dendrite, there are thousands of small projections called dendritic spines.

These little spines are very important because they make contact with spines of adjacent neurons. If you assume about a billion neurons in the human brain, and you multiply that by the power of the thousands of spines per neuron that can make, theoretically at least, contact with any other dendritic spine, you get a mind-blowing number of potential connections. You do the math, I can’t.

It is through these connections that information flows in the brain. Now you get the idea about the enormity of possibilities for information to be transmitted from one neuron to another and from one region of the brain to another, anatomically distant, region.

 

Plasticity of the brain

As if this is not enough, there is an added layer of complexity: Neurons can change the number and location of their connections to other neurons, by adding new dendritic spines, reducing them, or changing their position on the dendrite in response to experiencing new situations and the need to embed them in our memory. The consequences of this phenomenon are enormous because what it amounts to is not only an almost infinite capacity to store new information (memory), but also to learn from past stored experiences and apply this knowledge to coping with brand new experiences. In daily language, we call that intelligence.

 

The cell skeleton

How can the cell maintain its shape? How can the neuron grow new spines? The answer, my friends, is written in the cytoskeleton.

Yes, just like the skeleton is important in giving the body its shape, so does the cell maintain its shape with a complex molecule called actin. If you looked at the cell under the electron microscope, you’d discover that it is crisscrossed by thin filaments going seemingly helter-skelter in all directions. The filaments are made of actin molecules, and there is a method to their chaotic ways; they form a railroad system for the transport of proteins to their various destinations in the cell and they maintain the overall shape of the cell. They can also perform another important trick. They can depolymerize and re-polymerize again, namely, the filaments break down to their component actin molecules and reform new filaments going in a different direction altogether. This is the molecular basis for forming new spines. And you might even be as bold as to say that since the acquisition of memory and learning depends on the plasticity of the neuron, this is the very basic molecular mechanism of cognition.

Indeed, several studies have shown that in different conditions of mental retardation, the number of spines is markedly reduced, and there are abnormalities in the structure and function of actin filament. Suggestive, but not quite a proof.

 

Rho GTPases: A small molecule in the cell, a giant step for mankind

Attached to the neuron’s cell membrane are molecules call Rho small GTPases. But when it comes to their function, there is nothing small about them. They control the polymerization/depolymerization of actin filaments, which means that they control cell shape, and in the brain, it means that they control number and location of dendritic spines. In neurobiology and psychology, it means that they are major players in cognition!

 

CNF 1: Botox for the brain

CNF 1 puts the Rho GTPase 1 in a permanent state of activation. That means that actin is constantly in the polymerized state, forming new connections between dendritic spines, thus forming the anatomical “infrastructure” for memory formation and learning.

Are we entering the age of neurotoxins? Is CNF 1 a much more sophisticated Botox ( a neurotoxin as well) that is not skin deep but rather penetrates the depth of what makes us an intelligent being?

In the January 9th issue of the Proceedings of the National Academy of Sciences (PNAS, vol.104, pp.636-641, 2007), Giovanni Diana and his colleagues at the Instituto Superiore di Sanitá in Rome, Italy report that they injected CNF1 into brains of mice. They then proceeded to run the mice through various anatomical and physiological studies as well as tests for memory and learning. This is what they found:

  • Administration of the neurotoxin caused rearrangement of the cerebral actin cytoskeleton
  • Enhanced neurotransmission and synaptic plasticity
  • Improved learning and memory in various behavioral tasks

These findings are just as predicted from our knowledge of basic cell biology. Can the discovery of drugs mimicking the action of CNF1 be far behind?

I can’t help it but repeat my reaction to this study: WOW, AWESOME, and BRAVISSIMO!

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