Celebrities and politicians are known for their love of the spotlight. “Me, me, me!” are the words to get ahead by in our modern media circus. As well, it can even be – in the unglamorous world of science – where, in characteristically geeky form, the conventional wisdom is to shout, “my hypothesis, my hypothesis, my hypothesis!”. Once, for example, I had a grad school professor say she was not allowed by her department to teach about glial cells in her brain development class. Another distinguished professor once told me, “don’t even bother sending a grant in, if it is focused on white matter“. No sir, it appears that modern neuroscience shall only focus on one main hypothesis – the neuron doctrine and not on the lowly support cells (astrocytes, oligodendrocytes & microglia) that, actually, make up more than 90% of the human brain. Hmmm, who would have thought to find such a cult of neuronal celebrity in the halls of academia?
With this in mind, I really enjoyed the recent paper “Rett Syndrome Astrocytes Are Abnormal and Spread MeCP2 Deficiency through Gap Junctions” [doi:10.1523/jneurosci.0324-09.2009] by Maezawa and colleagues. The authors point out several critical gaps in the literature – namely that the expression of MeCP2 (the gene that, when mutated, gives rise to Rett syndrome) in neurons does NOT account for all of the many facets of the syndrome. For example, when MeCP2 is deleted only in neurons (in a mouse model), it results in a milder form of abnormal neural development than when deleted in all CNS cell types ( the full mouse syndrome: stereotypic forelimb motions, tremor, motor and social behavioral abnormalities, seizures, hypoactivity, anxiety-like behavior and learning/memory deficits). Also, it is not possible to reverse or rescue these deficits when a functional version of MeCP2 is expressed under a neuron-specific promoter. However, when re-expressed under its endogenous promoter – it is possible to rescue the syndrome (free access article).
The authors thus looked much more closely at the expression of MeCP2 and found that they could indeed visualize the expression of the MeCP2 protein in cultured ASTROCYTES – who are a very, very important type of support cell (just think of the personal secretary Lloyd to Ari Gold on the TV show “Entourage”). The team then examined how astrocytes that lack 80% of the expression of MeCP2 might interact with neurons – the very cells they normally support with secretions of growth factors and cytokines. It turns out that both normal and MeCP2-deficient neurons do not thrive when co-cultured with astrocytes that have weak MeCP2 expression. The team reports that dendritic length is reduced after a day and also a fews days of co-culture, suggesting that the MeCP2-deficient astrocytes are failing to provide the proper trophic support for their neuronal celebrity counterparts. Short dendrites are generally considered a bad-thing since this would predict poorer connectivity, and poorer cognition across the brain.
Hence, it seems that the lowly astrocyte is far more important in understanding what goes wrong in Rett syndrome. Ironically, in this case however, the celebrity status of the neuron remains untarnished as astrocytes can now be blamed for the consequences of MeCP2 mutations. The authors suggest that treatment of Rett syndrome via astrocytes is a worthwhile avenue of investigation. This new direction in the search for a cure will be an exciting story to follow!