One of the problems with depression as a disorder is that the symptoms never seem to manifest the same. To give you an idea of what I’m talking about, here are some of the DSM IV recognized symptoms of depression:
1) Insomnia or hypersomnia (not sleeping OR sleeping too much)
2) Having no appetite OR eating too much
3) Slowed motor movements OR motor agitation
(Source)
…you get where I’m coming from here. Some of the symptoms are universal, depressed mood most of the day, lack of pleasure in previously enjoyed activities, feelings of worthlessness or guilt. But it seems that every patient shows a different constellation of symptoms. And of course this makes diagnosis and treatment complicated. What scientists want to find is an underlying mechanism, an underlying problem that occurs in EVERYONE with depression (or at least in most people).
In order to find this, a lot of studies have looked at genes in people who had major depressive disorder (MDD) at time of death (often this involves comparing suicides to accidental deaths. It’s a really depressing kind of study to do, but we gotta look somewhere). Most of them have looked at very specific molecular targets, and a lot of them have ended up nowhere, though some have gotten somewhere.
But this study went all they way. They went ahead and did a whole genome expression analysis of depressed subjects and controls (post-mortem).
And they found something!
Duric et al. “A negative regulator of MAP kinase causes depressive behavior” Nature Medicine, 2010.
What they found was a protein called MKP-1. MKP-1 is a MAP kinase regulator (-1), and MAP kinase stands for mitogen activated protein kinase. These are proteins that response to stimuli (like growth factors, inflammatory factors, etc), and regulate cellular activities accordingly. There are a LOT of MAP kinases. Observe:
(From BioCarta. I LOVE BioCarta. I might have some of their stuff up as wall art)
So anyway, what they found to be dysregulated was a REGULATOR of MAP kinase, MKP-1. And by “dysregulated” they meant increased. It was increased in the hippocampus of the depressed patients, an area associated with memory, as well as the actions of antidepressants and depressive-like behavior in rodents.
But of course, just because MKP-1 is changed in the brains of depressed patients doesn’t mean that it CAUSES depression. It could be a side effect of medication, it could be a side effect of something else dysregulated in the brain, or a multitude of other things. To figure out how it related, they took rats, and made them depressed, using one of the best rodent models of depression: the chronic stress model.
The chronic stress model of depression is where you expose a group of rats to unpredictable stressors over and over again for weeks at a time. The stressors are in random order, and are kind of mild things like tilting the cage a bit for a while, putting the rat cage on a shaker plate, turning the lights on and off, changing the rat’s housing buddies, making them swim, putting the radio on too loud, making them cold, exposing them to predator odor, etc. No pain or physical harm, just stress. The stressors (there are usually ten or so) are done in random order, usually several times a day, for a good while. Considering the set up a lot of these require and the time spent, Sci would personally like to see a study on the effects of rodent chronic mild stress on the human researchers performing the experiment, but maybe that’s just me. Anyway, this stress model produces effects seen in human depression and other rodent depression models, including anhedonia, lack of preference for a sweetened solution, etc.
So they exposed them to a chronic stress paradigm and then looked at their MKP-1 levels.
So, all the bars are measuring mkp-1 mRNA (they have another graph measuring protein as well). The dark bars are chronic unpredictable stress alone. The white bars are chronic unpredictable stress and FLUOXETINE, an antidepressant, and the grey bars are fluoxteine alone. You can see that the dark bars are WAY up, showing that chronic unpredictable stress increased MKP-1, and the white bars are lower, showing that treatment with an antidepressant can reverse this effect.
But that still doesn’t show that MKP-1 is DIRECTLY RESPONSIBLE for depressive like behaviors in these animals, it just shows that it’s increased after a paradigm designed to create depressive like behaviors. SO. They took a viral vector and stuck it in the hippocampus of the rat brain. A viral vector is where we take a virus (often herpes simplex or lentivirus), and take out the nasty viral DNA that causes things like death. We then replace that DNA with the DNA we want (usually additionally tagged with something that glows so we can see it, and of course take journal cover worthy pictures as well). Then, when you inject the virus, the viral machinery gets your protein into the cells nearby, but instead of nasty virus protein, you are now expressing the protein YOU want with the DNA YOU put in. Neat system, yes? Stuff like this reminds me how much we live in the future.
(Source)
So they took this and put in the DNA for MKP-1, and artifically increased it in the hippocampus of mice.
(Observe the journal cover worthy glowy images)
What we’re interested in is on the bottom, where they ran depression tests on rats that had and had not received the virus. The animals with HIGHER MKP-1 (white bars) drank less sucrose, escaped nasty situations less well, and showed an increase in time to feed in a novel environment, all of which are tests used in antidepressant paradigms. It appears these rats act more “depressed”.
Of course, they had to do it the opposite was as well. So they used mice that had a knockout of MKP-1, and ran THEM in depression tests, following the chronic unpredictable stress I talked about above.
You can see the are the knockout mice (-/-) still drank more sucrose following chronic unpredictable stress, while control mice drank less (but no forced swim, tail suspension, escape, or novelty induced hypophagia, and those error bars are giant, as I might expect in this test…can I get another test? To Sci, this figure looks like it may have been thrown in at the end to appease the reviewers).
Be that as is may, the results are really pretty convincing. It looks like increases in MKP-1 may be correlated (and CAUSE!) depressive behavior in mice. This is a really great finding, I’m not gonna lie. It gives us a new idea for TREATMENT. For so long we scientists have been stuck with traditional antidepressants (like fluoxetine, used above) which target monoamine neurotransmitter systems (like serotonin, norepinephrine, and dopamine). While these drugs do work in some people, something like 40{9f43b4361d9a125bc126dd2a2d1949be02545ec69880430bc4fed2272fd72da3} of patients are left out in the cold and can’t find a treatment that works for them. Finding a unique target like this one, a protein that affects the expression of OTHER proteins, gives us a new protein to TARGET. We can try and make MKP-1 inhibitors that will work to decrease MKP-1 in the brains of depressed patients. We can examine people who don’t get depressed to see why they have no changes in MKP-1. Basically, it gives us a new opportunity, and until we cure it, we can always use more of those.
Duric V, Banasr M, Licznerski P, Schmidt HD, Stockmeier CA, Simen AA, Newton SS, & Duman RS (2010). A negative regulator of MAP kinase causes depressive behavior. Nature medicine, 16 (11), 1328-32 PMID: 20953200
