When it comes to manipulating your body with drugs, you have no better friend than your G-protein coupled receptors. G-protein coupled receptors (ok, you can call them GPCRs) are proteins embedded within the membrane that makes up the outer border of our cells, and their exposed cell-surface position makes them great targets for drugs. If you've ever taken Claritin, Zantac, beta blockers like Lopressor, oxytocin, epinephrine, Zyprexa, antihistamines, some anti-HIV drugs, opioids, cannabis, or merely consumed a caffeinated beverage, then you've medicinally manipulated some of your GCPRs. Nearly 1,000 of our 24,000 genes encode GCPRs, which testifies to the major role this class of proteins plays in our physiology.

Given the importance of these receptors, it is not surprising that an interesting new study is describing a GPCR which may play a role in brain size, memory, and social interaction, and mutations in this GPCR could play an important role in schizophrenia.

A group from the US National Institute of Health and Astellas Pharma in Japan took a look at a GPCR called SREB2, a protein which has been very well-preserved throughout the course of evolution. In fact, mouse SREB2 is almost completely identical to the human version of the gene, which is a good thing since it is much easier to study GPCRs in mice than it is in humans. In both mice and humans, this protein is very prominently present in neurons, and it turns out that SREB2 plays an important role in the brain. The group of researchers found that if you create mice with excessive amounts of SREB2, the brain weight of these mice dropped by almost 20%. On the other hand, mice whose SREB2 has been deleted from their genome have larger brains. We don't know exactly how this works, but its clear that SREB2 plays a critical role in brain development.

What's more interesting is the effect of SREB2 on mouse social behavior. Too much SREB2 apparently makes mice anti-social. How do you recognize an anti-social mouse? You measure the length of their whiskers, of course. Just like chimps bond by grooming each other, mice socialize with each other by trimming their cage-mate's whiskers. When you look at a group of mice that interact normally with each other, you find that their whiskers are short. Mice that don't interact socially don't trim each other's whiskers. Mice with too much SREB2 have long whiskers - a sign that they don't interact very well with each other.

These anti-social mice with too much SREB2 have other odd traits, including brain morphology and memory problems that resemble strains of lab mice that are used to study schizophrenia. This interesting coincidence - that too much SREB2 makes mice similar to 'schizophrenic' mice (they aren't really schizophrenic of course; they are a useful animal model for studying aspects of the human disease) - led the group of researchers to wonder whether SREB2 plays a role in human schizophrenia. They looked at variants of the SREB2 gene in schizophrenic patients, to see if they could find any variants that correlated with brain changes. One innocuous DNA change in the SREB2 gene (an 'A' instead of a 'G' in one spot) appeared to be connected with a reduced amount of gray matter in some schizophrenic brains.

How this little change affects SREB2, and just what SREB2 is doing in the brain is still unknown. This GPCR, so well-preserved from the constant erosion of evolution change, has been playing an important role in vertebrate brains, many very different vertebrate brains, for hundreds of millions of years. It clearly has complex effects on how mice behave. Given our success at manipulating GPCRs with drugs, this study provides a potentially important lead in our effort to understand schizophrenia and opens a new opportunity to treat it.

Technorati Tags: Genetics g-protein coupled receptors schizophrenia brain