Researchers at Johns Hopkins restored the normal growth of specific nerve cells in the cerebellum of mouse models of Down syndrome (DS) that were stunted by this genetic condition. The cerebellum is the rear, lower part of the brain that controls signals from the muscles to coordinate balance and motor learning.
The finding is important, investigators say, because the cells rescued by this treatment represent potential targets for future therapy in human babies with DS. And it suggests that similar success for other DS-related disruptions of brain growth, such as occurs in the hippocampus, could lead to additional treatments - perhaps prenatally - that restore memory and the ability to orient oneself in space.
DS is caused by an extra chromosome 21, a condition called trisomy - a third copy of a chromosome in addition to the normal two copies. Children with DS have a variety of abnormalities, such as slowed growth, abnormal facial features and mental retardation. The brain is always small and has a greatly reduced number of neurons.
A report on the Hopkins work with trisomic mice, led by Roger H. Reeves, Ph.D., professor in the Department of Physiology and the McKusick-Nathans Institute for Genetic Medicine at Hopkins, appears in the January 24 issue of the Proceedings of the National Academy of Sciences (PNAS).
Reeves and his team used an animal model of DS called the Ts65Dn trisomic mouse to show that pre-nerve cells called granule cell precursors (GCP) fail to grow correctly in response to stimulation by a natural growth-triggering protein. This protein, called Sonic hedgehog (Shh), normally activates the so-called Hedgehog pathway of signals in these cells. These signals stimulate mitosis (cell division) and multiplication of the cells in the growing, newborn brain, according to the researchers.
The GCP originate near the surface of the cerebellum and migrate deeper into the brain to form the internal granule layer (IGL), the researchers note. Therefore, the team studied the growth of the cerebellum in Ts65Dn trisomic mice at seven time points -- beginning at birth - to determine when GCP abnormalities first occurred. The IGL was similar in both normal and Ts65Dn mice at birth, but was significantly reduced in the trisomic mice by day six after birth.
Furthermore, the researchers found that the reduced number of GCP in these mice compared to normal mice was not due to cell death; rather, there were 21 percent fewer GCP undergoing cell division in Ts65Dn mice. This suggested that stimulating these cells might restore normal numbers of GCP, according to Reeves.
The Hopkins team then showed in test-tube experiments that GCP from the brains of Ts65Dn mice had a significantly lower response to increasing concentrations of a potent form of Shh called ShhNp. That is, increasing concentrations of ShhNp triggered increasing rates of mitosis. Despite their lower response, trisomic cells did show a dose response with increasing ShhNp concentrations.