Tuesday, February 23, 2010

Misguided neurons play role in Autism spectrum disorders

In a newly developing nervous system, there is a constant jumble of activity: Cells are growing and dividing, chemical signals are diffusing through tissues, and neurons are trying to reach their targets and maintain connections that will be used and strengthened later in the developmental process.

All of these things are happening in the same space, at roughly the same time, and it can get a bit confusing for the neurons.

The confusion is usually kept under control when cells match: One gives off a chemical signal that will help sustain the growing axons of new neurons; the chemical attracts and promotes the growth of the target neurons. This chemically-released signal is called a neurotrophic factor, and its presence is essential for the organization and proper functioning of the developing brain.

However, if this process of matching goes awry, the developing brain can run into problems: Neurons will grow wild, connections that should be made don't get made and connections that should be weeded out thrive. Chaos can ensue, and the end product is usually malfunction.

Now there is some evidence that exactly this process might be to blame for some part of the malfunctioning seen in some Autism spectrum disorders. Autism and related disorders, which comprise a highly varied spectrum of symptoms and severity, are generally characterized by impaired social abilities, as well as demonstrations of repetitive behaviors.

Scientists at Hopkins and the University Medical Center in the Netherlands have been trying to explain this varied and often debilitating spectrum of disorders at the cellular level by looking at how the brain's neurons grow and develop - as well as how they navigate through the brain to find the proper targets with which to make the proper connections that will be strengthened with use later in life.

As Alicia Degano, R. Jeroen Pasterkamp, and Gabriele Ronnett and others have begun to realize, in Autism spectrum disorders, including Rett Syndrome, which is on the spectrum, neurons aren't getting to where they need to go. They aren't making the right connections. They aren't coming together to form nerve tracts, and they aren't being guided to their proper target cells. These Hopkins researchers believe that this malfunction can be tied to a mistake in one gene, called MeCP2.

MeCP2 is involved in turning off gene expression when not needed in development. Degano and her colleagues believe that when MeCP2 doesn't work, or when it works improperly, neurons first will not develop their tips (which can become either dendrites or axons), and then later will not form the necessary connections with other neurons due to malfunctioning axon guidance. Both deficits are crippling to cells that depend on proper connections for both survival and function.

The team studied patients with Rett syndrome as well as mice with an analog disorder. In particular, they chose to study the olfactory system because neurons in the olfactory system can regenerate, which makes it easy to take one or two to study. And by being able to study neurons not just in the mouse model, but also in the actual human disorder, Degano and her fellow scientists have been able to make unparalleled comparisons of the two disorders.

Indeed, they have found out that the two models are highly similar, thereby proving the olfactory system to be an excellent site for the study of Rett syndrome and related disorders.

The similarities across species are dramatic: In both human olfactory neurons as well as in those of small mice, axons are seen to project wildly from their parent neurons outside of the bounds of normal neural tracts. This misguidance is due to the loss of chemical signaling that tells axons where to grow and how to get there.

Also, the team has observed that besides just leading to simple misguidance, MeCP2 malfunction actually alters the levels of chemical signals that are expressed in the developing brain; it is most likely due to these altered levels that targeting and connection goes so badly awry.

This study, while helpful in understanding the mechanism of Rett syndrome and of other Autism spectrum disorders, is merely a stepping stone for Degano and her fellow scientists. They plan to perform further studies to investigate which chemical signals in particular are implicated in the malfunction seen in Rett syndrome as well as to further develop their understanding of the present findings.

Source: The John Hopkins News-letter

No comments: