A neuroscientist at Johns Hopkins has unlocked the mystery of how mammals control their brain circuitry by combining a truly old school research technique with modern molecular genetics. The technique dates back 136 years and when applied to modern molecular genetics technology Dr. David Ginty has been able to see how a mammal's brain shrewdly revisits and reuses the same molecular cues to control the complex design of its circuits.
Details of the observation in lab mice, published Dec. 24 in Nature, reveal that semaphorin, a protein found in the developing nervous system that guides filament-like processes, called axons, from nerve cells to their appropriate targets during embryonic life, apparently assumes an entirely different role later on, once axons reach their targets. In postnatal development and adulthood, semaphorins appear to be regulating the creation of synapses, those connections that chemically link nerve cells.
"With this discovery we're able to understand how semaphorins regulate the number of synapses and their distribution in the part of the brain involved in conscious thought," says Dr. Ginty, a professor in the Neuroscience Department at the Johns Hopkins University School of Medicine and a Howard Hughes Medical Institute investigator. "It's a major step forward, we believe, in our understanding of the assembly of neural circuits that underlie behavior."
Because the brain's activity is determined by how and where these connections form, Ginty says that semaphorin's newly defined role could have an impact on how scientists think about the early origins of autism, schizophrenia, epilepsy and other neurological disorders.
The discovery came as a surprise finding in studies by the Johns Hopkins team to figure out how nerve cells develop axons, which project information from the cells, as well as dendrites, which essentially bring information in. Because earlier work from the Johns Hopkins labs of Ginty and Alex Kolodkin, Ph.D., showed that semaphorins affect axon trajectory and growth, they suspected that perhaps these guidance molecules might have some involvement with dendrites.
Kolodkin, a professor in the Neuroscience Department at Johns Hopkins and a Howard Hughes Medical Institute investigator, discovered and cloned the first semaphorin gene in the grasshopper when he was a postdoctoral fellow. Over the past 15 years, numerous animal models, including strains of genetically engineered mice, have been created to study this family of molecules.
Using two lines of mice -- one missing semaphorin and another missing neuropilin, its receptor -- postdoctoral fellow Tracy Tran used a classic staining method called the Golgi technique to look at the anatomy of nerve cells from mouse brains. (The Golgi technique involves soaking nerve tissue in silver chromate to make cells' inner structures visible under the light microscope; it allowed neuroanatomists in 1891 to determine that the nervous system is interconnected by discrete cells called neurons.)
Tran saw unusually pronounced "spines" sprouting willy-nilly in peculiar places and in greater numbers on the dendrites in the neurons of semaphorin-lacking and neuropilin-lacking mice compared to the normal wild-type animals. It's at the tips of these specialized spines that a lot of synapses occur and neuron-to-neuron communication happens, so Tran suspected there might be more synapses and more electrical activity in the neurons of the mutant mice.
The researchers tested this hypothesis by examining even thinner brain slices under an electron microscope.
The spines of both semaphorin-lacking and neuropilin-lacking mice were dramatically enlarged, compared to those of the smaller, spherical-looking spines in the wild-type mice. In wild types, Tran generally noted a single site of connection per spine. In the mutants, the site of connection between two neurons was often split.
Source: Johns Hopkins University
Writer: Walaika Haskins