What do the overconsumption of food and Obsessive-Compulsive Disorder (OCD) have in common? At first, this sounds like a trick question. But deep in the brain, the molecules underlying our behavior may come together for these two conditions.
The first is MC4R, a receptor for melanocortin. It binds hormones and affects feeding behavior, mutations in MC4R are associated with severe overcomsumption of high fat, high calorie foods and with obesity. A mouse without an MC4R gene will become severely obese compared to its wildtype counterparts.
SAPAP3 is a protein that is associated with synapses, the spaces between neurons. It can regulate things like receptor levels that determine how well a neuron responds to excitatory input. But a knockout of SAPAP3 in mice produces something very different: severe overgrooming, a model of OCD. All rodents groom themselves, it’s necessary to keep clean. But SAPAP3 knockouts groom themselves far, far too much, to the point of creating terrible lesions on their skin. This has been proposed as a model of OCD, as many people with OCD become obsessed with cleanliness, and will do things like, say, washing their hands, to the point of severely damaging their skin.
So a knockout of MC4R creates obese mice. A knockout of SAPAP3 creates overgrooming mice. You might think that if you combined the two knockouts, you would get severely obese mice that also overgroomed.
But you don’t. Instead, you get mice that, to all appearances, seem completely normal. No obesity. No overgrooming.
Xu et al. “Double deletion of melanocortin 4 receptors and SAPAP3 corrects compulsive behavior and obesity in mice” PNAS, 2013.
(Warning: there is a figure below of an over groomed mouse. It’s not a pretty picture)
Why did the authors combine these two types of mice in the first place? It’s all because of the brain area known as the striatum. The striatum, in humans located near the center of the brain, ahead of the thalamus, plays many important roles in behavior such as reward in response to food, as well as in compulsory behaviors. So for example, MC4R receptors in the striatum may play a role in stress (MC4R plays a role in feeding of course, but its thought that is localized to the hypothalamus). SAPAP3, however, is also in the striatum, but it plays a role in synapse function. Because both of these proteins were localized to the striatum, the authors wanted to look at the combined effects, to see how the two pathways might interact.
They bred the mice together to create mice that were totally normal, mice that were SAPAP3 knockouts, mice that were MC4R knockouts, and mice that were knockouts for both proteins. Then they assessed them for obsessive grooming behaviors.
What you can see above is part of Figure 1, show the grooming time over 24 hours in all of these mice. You can see in the second bars from the left in both graphs (and the second mouse profile on the left), that the poor SAPAP3 knockout mice really REALLY overgroom. It’s painful to see, and you can see from the bar graphs that they spent a lot more time grooming than the other mice do. If you look at the MC4R knockout mice, they don’t have grooming problems at all (third mouse from left), and if you look at the knockout for BOTH SAPAP3 and MC4R…it’s just fine too! (Mouse on the right).
But when you knockout both SAPAP3 and MC4R, the overgrooming is not the only problem that gets solved. MC4R knockout mice are obese, they consume a lot more food and weigh a lot more than their wildtype brothers. But when the MC4R knockout was combined with the SAPAP3 knockout, not only did the mice stop overgrooming…they stopped over eating.
On the left you can see the MC4R knockout, and on the far right, you can see the double knockout for MC4R and SAPAP3. While the MC4R knockout is much bigger, the MC4R and SAPAP3 knockout is about the same size as the wildtype.
So each knockout creates a problem, one creates overgrooming, the other creates obesity, but putting the two problems together…appears to create a solution. 1 + 1 = 0.
Why? It could be a matter of signaling in the striatum.
The striatum is involved in compulsive behaviors and also in overeating. The SAPAP3 knockout, which causes compulsive overgrooming, is associated with decreases in excitatory signaling in the striatum. The MC4R knockout is also associated with similar changed. But when you knockout both, the signaling goes right back…to normal (the trace on the far right).
Why is this the case? Why do two negatives cancel each other out? It’s tough to say. It could be that SAPAP3, which plays a role in the synapse and therefore in synaptic plasticity, also plays a role in the MC4R control of body weight. And that the MC4R plays a role in synaptic plasticity. The two pathways could come together.
And this could end up making sense. SAPAP3 plays a role in a compulsive behavior: overgrooming. In a similar way, MC4R plays a role in compulsive behavior: overeating. But HOW these two proteins interact? So far, we don’t know. But if we begin to understand the pathways, we could begin to understand both overeating and overgrooming, and may be able to find new drug targets to treat OCD and genetically induced overeating. These two seemingly different things might not be so different after all.
Xu, P., Grueter, B., Britt, J., McDaniel, L., Huntington, P., Hodge, R., Tran, S., Mason, B., Lee, C., Vong, L., Lowell, B., Malenka, R., Lutter, M., & Pieper, A. (2013). Double deletion of melanocortin 4 receptors and SAPAP3 corrects compulsive behavior and obesity in mice Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1308195110