The fine art of brain development pg. 6
The complex process seems to require an almost inconceivable number of “coincidences.”
“You have to have a signaling cell and a receptive cell in register at the same time, the same place, and also of the same ‘flavors,’” Broadie notes. These “flavors” are the neurotransmitter systems expressed by the cells. A neuron that produces dopamine, for example, needs to connect with cells that possess a receptor for the neurochemical.
Broadie uses the fruit fly Drosophila to dissect all aspects of the life cycle of the synapse: how it’s made, how it works, and how it changes throughout the organism’s lifespan. One way he does so is in the context of a disease called fragile X syndrome, in which synaptic development and/or function goes awry.
Fragile X disease, the most common inherited form of mental retardation, causes a structural overgrowth of dendrites and axons during development, as well as functional abnormalities in synaptic plasticity later in life.
“There’s no question in my mind that fragile X is a disease of development,” says Broadie. “But there is a real split in the field whether it is primarily a disease of development, a disease of plasticity, or both.”
The answer is vital to developing intervention strategies, Broadie says. “If you want to fix the problem, you absolutely have to know where the problem is—or when the problem is.”
Fragile X in humans is caused by altered expression of a gene called FMR1 (fragile X mental retardation 1) resulting in the loss of its protein product, FMRP. Broadie and colleagues have developed a Drosophila model of the disease and have used the fly model to examine the developmental roles of FMRP.
They’ve found that FRMP is most highly expressed during a brief window of time during late brain development, and that the protein’s expression is increased by sensory input. Their work shows that FMRP plays a critical role in limiting axon and dendrite growth, in particular the activity-dependent “pruning” of neuronal branching, which is vividly illustrated in the overgrowth of neuronal processes and abnormal synapse formation in flies lacking the protein.
“If you compare a fragile X mutant brain to a normal brain, there are fairly severe problems in things like nerve cell structure and synapse formation,” Broadie says. “But—and here’s the crux of the problem—most of those defects go away.” In mouse models of fragile X, he says, after the first month following birth, their brains look fairly normal.
Even though the structural abnormalities appear to go away, the functional problems associated with fragile X persist. Even though the synapses look normal, he notes, it is unclear whether they function properly.
The dynamic brain
So while the link between altered brain development and the later problems associated with fragile X is being resolved, Broadie and others are already finding factors that might be exploited to improve the symptoms of fragile X.