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Chapter 10:  All the Players on One Stage

Summary:   You've seen the stress factors (cortisol, CRF), and the trophic factors (BDNF and friends).  This chapter slowly assembles the "complete picture", as it is currently understood, in one diagram:  from stress factors to trophic factors, and what we know so far of how medications affect that balance.  

Acknowledgement:  This chapter again presents the work of Dr. Husseini Manji (profiled at the beginning of Chapter 6) and his team of researchers at the NIMH, this time even more directly, as these diagrams were developed from their drawings.  

Link to Chapter 11


Regulating Cell Growth

As you've learned, cells regulate their size, and the number of synaptic connections they make, through two sets of regulatory molecules: 

Most of these are proteins, whose production in controlled by the cell nucleus.  You can think of this regulation as like a farmer, who is constantly deciding what to plant and where; and whether to buy more land, when things are good.  Or, he might be forced hold back on planting, or sell land, when times are tough.  Watching a very active farm over decades, you'd see it grow and shrink; change it's color, with new crops here and fallow fields there; and at the center of it all would be the farmer, making decisions about what to do next, depending on the overall needs of the farm. 

At the center of neuron "decision-making" is a regulatory process, which determines what proteins to make at what times: how much growth factor, and how much "tear-down" factor.  As you know, proteins are made by unfolding a portion of the DNA, the genetic code, and copying the instructions for making a particular protein.  So the regulation process conducted primarily in the nucleus.  In our analogy, the nucleus is like the farmer's office in the farmhouse, where he keeps the maps and records of the farm, and where he makes decisions based on that information, as well as information coming in from the bank, and the weather station, and from his wife with the Ph.D. in Engineering.  From that office come the decisions on planting, or selling off land, etc.    

But the seesaw balance between trophic and atrophic factors takes place out in the cell soup, and particularly in one part of the cell, a set of small "organelles" (little organs within the cell) called the mitochondria.  

Ultimately we are going to end up with a jigsaw puzzle of a diagram, but please have faith, and don't be frightened.  You're going to see many small pieces separately before we put this all together.  Here's the main point, if you get lost:  brain chemistry researchers have already gone a very long way, far beyond knowing which neurotransmitters seem to be involved, toward understanding how depression works!  You will be able to see that, even if the abbreviations and arrows below make sense or not -- if you must, think of these diagrams as roadmaps, and that all you need to see is how many highways have already been built.    

Let's start with our model farm:

Tear-down (Atrophic) Factors

At least two different processes have been shown to be involved in cell atrophy and death:  a decrease in fuel supply, through decreased glucose transport; and death of the power supply of the cell, the mitochondrion.   In our analogy, this is like the farmer running low on money:  because he can't spend much on maintenance, he can't run the fuel truck but half the time, and his generator keeps breaking down.  Here's what it looks like in cellular terms, with the "bad guys" in red:

(in this and all subsequent diagrams, arrow tips indicate an action which increases an effect; and ball tips indicate an action that decreases an effect.  For example, in this diagram, the ROS effects are arrow tips; and the GR effect is a ball tip.  I'm sorry that my slides don't show up very well here; I know it's tough to see what tip you're looking at! But you should be able to follow that easily in the text, and the main point is to recognize the interplay of "good guys and bad guys", as you'll see below.)

The Powerhouse.  Under stress conditions, calcium (Ca++) increases inside the cell.  You'll see in a moment why.  It goes into the mitochondria, along with other places in the cell.  This accelerates a process governed by a molecule named "Bad" -- an appropriate name in this case, short for Bcl-2ľassociated death protein.  Really.  This is pretty high drama for biochemists. (You'll meet Bcl-2 itself shortly.) 

Stress conditions also increase factors (not all of which will be shown here) that lead to loose oxygen radicals, called "reactive oxygen species", or ROS in the diagram.  These normal products of cellular metabolism can be very destructive when freed from their bindings in the mitochondrion -- like Farmer Jones' bulls, on the loose!  Not good.

Bad and several other molecules which serve the "tear-down" role, join together to open a pore -- a hole -- in the wall of the mitochondrion.   This hole is called the PTP, the permeability transition pore.  Bad basically opens the mitochondrion's walls, fluid pours in, and the poor thing bursts.  Not good.  Not good for Farmer Jones either, when the generator don't run anymore. 

The Fuel Truck.  Glucose Transporters help glucose get where it needs to go inside the cell.  Fewer or less effective transporters means less fuel available where it is needed.  Not good.  In our diagram, you can see that the stress hormone cortisol (see Chapter 8) is responsible for this shift, through its receptor GR, the glucocorticoid receptor.  Together, they substantially decrease the effectiveness of glucose transport. This leaves the cell short on fuel, making it less active.  Since electrical activity is required to maintain synaptic connections with other neurons (sort of a use-it-or-lose-it arrangement), this downshift is part of the shrinking of connections you saw in Chapter 7. 

Wait, where did that calcium come from?  One molecule that plays a role in calcium excess is a neurotransmitter you may not be familiar with:  glutamate.  This is one of the major "excitatory" neurotransmitters in the central nervous system.  However, in many conditions, including seizures and mood disorders, it looks like too much glutamate is a very bad thing.  It overexcites cells to the point where they can actually die.  Their death follows from one of the ways glutamate works: it allows calcium to enter the cell.  Remember, we just saw that too much calcium in the mitochondia can lead to their death.  Thus too much glutamate can shut down the powerhouse.  We'll just add that to the picture we've developed thus far: 

Glutamate is a key neurotransmitter in the molecular and cellular changes that store new memories, so it is crucial in learning.  But as we've seen before, too much of a good thing -- becomes a bad thing.  

We turn now to the other side of the atrophy/cell growth balance, the trophic factors you met in Chapter 9 -- along with some others as well.  

Growth Factors

You've met several of these before.  Now you'll get a chance to see how they fit in the cellular picture.  Remember, if it gets confusing, ignore all the arrows and keep your eye on the big green and red labels, the trophic and the atrophic factors respectively.

Again you see the trophic factors BDNF and Bcl-2 (green boxes).  You see the intermediate proteins which lead to increased CREB  from the neurotransmitters serotonin and norepinephrine (NE), as presented in Chapter 9.  Here the many links in each chain have been represented by a single molecule:  PKA in the NE pathway, and MAP/ERK in the serotonin pathway.

There is CREB, acting in the nucleus, leading to more BDNF.  But now we also see two actions of BDNF, through the MAP/ERK system: 

  1. BDNF decreases the activity of Bad (see the ball tip on that arrow?).

  2. BDNF also stimulates the production of Bcl-2.

Remember that Bcl-2 is itself a trophic factor.  It stabilizes the membrane of the mitochondrion so that Bad is less able to cause trouble there.  Thus, you can see that BDNF works two ways, increasing a protective factor and decreasing the activity of a destructive one.

Mind you, cell "destruction" is not such a bad thing as it sounds.  This is how cells remodel themselves.  Farmer Jones may decide to tear down a fence, or even sell off a piece of land, so as to increase production on some other part of the farm.  But if the balance of growth and destruction shifts too far toward tearing things apart, ultimately the cell will die.  Too much of a normal thing becomes a bad thing.

How Lithium Works in Mood Disorders (bipolar and major depression)
(
If you're starting to feel overwhelmed, this next section is not necessary for a good "big picture" view.  You could just skip ahead for one last important addition.)

For a look at one of several pathways affected by lithium and another mood stabilizer called valproate (Depakote), we need to add one more serotonin effect.  Serotonin also inhibits the actions of Bad through another pathway, shown here:

Look closely and you'll see that just two more molecules have been added , creating a new inhibitory (ball tip) pathway to Bad.  One (phosphatidylinositol-3 kinase)acts on inositol , which of interest because this "natural" molecule has some antidepressant properties.  This pathway also allows us to place on our map one more atrophic factor, GSK-3β.  You don't have to remember that name, of course.  Why, Farmer Jones wouldn't likely have the slightest idea (unless his wife had bipolar disorder and he'd been staying up late trying to understand the molecular basis of lithium action).  GSK-3β is of interest because lithium and valproate both inhibit it, as shown in the next diagram. 

GSK-3β is Glycogen Synthase Kinase, which is known to play two roles: one in fuel metabolism, especially in muscle tissue; and one in the pathway we see here, participating in the regulation of cell "apoptosis", the fancy Greek term for cell death pathways. Note that GSK-3β inhibits the green pathway from serotonin to Bad.  But inhibition of GSK-3β is just one of several ways lithium shifts the balance of atrophy and cell growth.

Lithium works at several other points in these chains, including BAG-1, which appears in the frame below as another white hat (er, green rectangle, that is -- shown below at the top of the heap, increasing Bcl-2, another good guy; and decreasing activity of the cortisol pathway, in pink at the top).    Lithium increases levels of this BAG-1, which is discussed further below.  

The bottom line on lithium then:  it works in many different places, all shifting the cell toward increased growth and activity, and more resilience in the face of molecular stressors like cortisol.  In fact, it seems so powerful in this respect that it is being studied in other conditions where neuron atrophy is a problem, including Alzheimer's Dementia, Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's disease), and even trying to get neurons to grow connections after injury.  We'll see lithium's effects on mood-based atrophy in Chapter 11.  

One More Trophic Factor: The First Discovered Deliberately

Getting a bit complex now, isn't it?  Courage:  we have only one more major trophic factor to add to this picture, and then we can put the whole thing together. 

In the next diagram, you'll see the glucose transporter back in the picture (remember that, the fuel truck from earlier?), and the way it is affected by cortisol, as we saw before.  But now we've added a new trophic factor, BAG-1.  You can see it here, inhibiting the negative effects of cortisol and increasing the effects of Bcl-2

BAG-1 is among the very first molecules, among the many we've seen here, which was identified because the researchers knew what to look for!  Dr. Manji and his NIMH team looked at the molecular results of effective mood medications.  Two medications that have been very effective in the treatment of bipolar disorder are lithium and valproate (the latter is an antiseizure medication; one version in the U.S. is called Depakote).  They asked: "what do lithium and valproate both do to neurons?"  They hoped this would lead to more clues about the cause of mood disorders, as well as possible new medication approaches. 

Their results were very dramatic (sometimes you can hear a scientist's pride and delight even when he is just walking you through a set of research results).  The NIMH team looked at the genetic information that was being used ("transcribed") by the cell's DNA-reading machinery under normal conditions, then when lithium was added, or when valproate was added.  They looked for segments of the genetic information in the cell (genes) which became active and were copied only when the neuron was exposed to these medications.  Then they simply looked for genes that were activated under both conditions:  first on exposure to lithium, then on exposure to valproate. 

At this point, the hunt for key genes was simpler than reading the bar codes at the grocery store.  You might even be able to do it yourself!  Which of the following "bar codes" have a dark band in the same place on the lithium readout on the left; and the valproate readout on the right -- but not on the salt water control readout in the middle?  Ignore the yellow arrow for now.

The yellow arrow band is not what we're looking for, right?  That one only shows up clearly for lithium.  There are some other dark bands on both lithium and valproate strips, but most of these also show up on the control strip in the middle, indicating that this was not an effect specific to the medications.  There are only two bands, in the upper third of the strip, marked slightly to highlight them, which are shared by both lithium and valproate but not by the control condition.  One of those is BAG-1. 

Of course this simple read-out is the result of years of work developing these lab techniques.  But can you imagine how exciting it was for the NIMH team to line up these strips and look, with the naked eye, for the match, as you just did?  However, then began the difficult task of determining just what gene this was, and what exactly the gene's protein product does in the neuron.

Ultimately they identified the protein as "Bcl-2 associated athanogene", or BAG-1.  Slowly they worked out this molecule's role in the story described here: a blocker of the cortisol effect, and helper to the cellular growth factors.  The researchers noted that these discoveries have "the potential to lead to the development of novel therapeutics", an understated acknowledgement that medications could be developed from their work -- medications which might be more directly effective than our current treatments, because they would have their effects closer to the ultimate molecular targets described here. 

Putting It All Together

Finally now we can take one (frightening?) look at the entire collection of factors discussed here, if only to show you how much work you've done, trying to follow all this -- but also to show you in a single glance just how much has been learned about how mood disorders "work" at the level of molecules.  I find this a message of great hope and encouragement, especially knowing that the NIMH research team, and many other similarly dedicated molecular researchers, are chasing this story toward a level of understanding that will could to highly effective treatments with low risks, and perhaps someday to knowing how severe mood disorders can be prevented. 

 

Now on to Chapter 11, the last in this series