Brain Organization Factors Are Found by JAX



BAR HARBOR — A Jackson Laboratory research team led by associate professor Robert Burgess has shown that two proteins, called DSCAM and DSCAML1, are essential to the proper arrangement (what scientists call “mosaicism”) of neuronal circuits in the retina. The finding could light the way to understanding a wide range of neurodevelopmental defects.

 

Acting as a kind of mortar in the brain mosaic, DSCAM and DSCAML1, which already have been implicated in brain development in fruit flies and birds, appear to exert just the right attractive and repulsive forces to ensure that neurons of the same type form well-defined synaptic connections.

In research published in the journal Neuron, Dr. Burgess and his colleagues show that in the absence of DSCAM, retinal neurons do form synapses, but they clump together without the regular spacing needed to ensure an absence of gaps in the brain circuitry. In other parts of the brain, such clumping could underlie a number of disorders, including Tourette’s syndrome and Down syndrome – in fact, DSCAM stands for “Down syndrome cell adhesion molecule.”

A commentary essay by Stanford University neurobiologist Andrew D. Huberman hails the researchers’ work, noting that they provide “clear answers” to questions about the role of DSCAM “and in doing so, unveil a remarkable aspect of the adhesion code that underlies neuronal circuit wiring.”

Like any home wiring project, Dr. Burgess notes, adhesion is an important component. “If you want to connect this electrical circuit to that one, you string a wire between them, put the wire nuts on them, label the circuits and then you need some kind of adhesive to glue them together. We went into this thinking we were going to find the ‘glue,’ and what we actually found is the stuff that seems to keep the glue from going haywire.”

Studying a mouse that doesn’t produce DSCAML1, the scientists realized that the protein is the nonstick “stuff” that prevents brain cells – in this case, retinal neurons – from clumping together like overcooked spaghetti. Dr. Burgess says that the retina, with its well-understood structures, “is a great place to start, because we have all the ‘labels’ or markers and know where to look,” Dr. Burgess says. “What we’ve shown in the retina provides a new way to look for neurodevelopmental disorders elsewhere in the brain, in animal models and human patients.”

Dr. Burgess notes that DSCAML1 maps to a region of the human genome that is associated with Tourette’s syndrome, and adds that too much or too little DSCAM or DSCAML1 could turn out to have a role in many other disorders such as Down syndrome, autism and schizophrenia.

“What these disorders share is that there’s nothing really grossly wrong with the brain – all the major parts are there and are more or less connected the way they should be, with some minor abnormalities. Now we can start to investigate specific individual cell types in the brain and ask whether they’re properly spaced, as a first step to understanding syndromes associated with those cell types.”

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