My favorite obsessive compulsive detective, Monk, may never clear up the mystery of who killed his beloved wife, but scientists are closer to clearing up the mystery of why Monk is obsessive compulsive. The new discovery is that mice who are missing a protein called SAPAP3 act like they, too, have OCD (obsessive compulsive disorder). They do not boil their toothbrushes before using them or wash their hands 100 times, of course, but then the compulsive behaviors of humans vary quite a bit from individual to individual anyway. Just like humans, these OCD mice exhibit what looks like an unhealthy obsession with cleanliness. They lick and groom themselves to the point of destroying their fur, and damaging their skin. They do this even when they should be sleeping. They do not solve mysteries, so far as we know.
How is it that these mice were missing that particular protein? Well, these are very special mice. They have been genetically engineered. Specifically, the gene that codes for SAPAP3 has been removed, or “knocked-out” of their DNA. We can call them SAPAP3 knock-out mice. And they were created for that best of scientific reasons: the researchers just wanted to see what would happen if you took that gene out.
This story should raise a lot of questions in the minds of readers who do not have a lot of background in genes and behavior.
Q: What does knocking out a gene affect a particular protein?
A: We think of genes as just being a kind of code, that passes on information about traits from parents to children. But in fact, genes are much more than that. They are protein factories. What you inherited from your parents are 23,299 little protein-building machines. It is the proteins they build that do the work of every cell in your body. Different kinds of cells get different proteins, because different genes are switched on and off for different cells. So these SAPAP3 knock-out mice have had the genes for that one protein effectively turned off for every cell.
Q: Why does a protein affect grooming behavior?
A: Like any behavior, grooming involves a great many neurons (nerve cells). Neurons “talk” to each other by means of chemicals called neurotransmitters. One neuron releases a neurotransmitter, and the next one picks it up. SAPAP3 plays a role in the transmission of the neurotransmitter glutamate. What brain circuitry is being messed up by the lack of SAPAP3 is not clear. Since glutamate is an excitatory neurotransmitter used all over the nervous system, there are many possibilities. So we know that the lack of SAPAP3 is interfering with the normal function of the nervous system, but we do not know exactly what it does to increase grooming.
I should also point out that the neurotransmitter more often associated with OCD and other anxiety related disorders is serotonin.
Q: Is there anything that can be done for these poor mice?
A: Yes! As it turns out, they respond to fluoxetine (prozac). This drug, which is also used to treat OCD in humans, significantly reduced their grooming behavior. This drug is a serotonin specific reuptake inhibitor (SSRI), which only makes the glutamate connection more puzzling.
Q: Is Adrian Monk an SAPAP3 knock-out human?
A: Not in the same way as the mice. He has not been genetically engineered. But it is possible that natural genetic variations among humans contribute to OCD. It is also possible that lower production of this protein is involved in OCD in humans, but we will need new studies to look at this.
Something to keep in mind whenever you read a story about a gene that has been identified with this or that disorder: Just because the gene plays a role in some individuals does not mean that the same gene plays the same role in everyone. There might be multiple genes involved. There might be many pathways to the same illness. In fact, it is an entirely different gene linked to OCD that most researchers have been focused on the past several years.
One thing is clearly different between mice and men (at least OCD mice and men): For these mice this is purely genetic. In humans, it may be a mix of genes and experience. In some humans, that experience may be a strep throat, which then triggers an autoimmune response. Family dynamics and life stress certainly play a role in the ups and downs of OCD, but probably not in creating it.
Finally, it is worth pointing out that the mice’s behavior might not really be analogous to OCD in humans. OCD is one kind of anxiety disorder, but not the only kind. Self-grooming is a way to calm anxiety. Then again, so is touching every parking meter on the sidewalk as you go by, if you are Adrian Monk.