Extra Copy of Nervous System Gene May Contribute to Down Syndrome, UMich Team Finds

An extra copy of a gene involved in nervous system development causes overgrowth of certain inhibitory neurons in the neocortex, potentially contributing to Down syndrome, according to a study appearing this week in PLOS Biology. The finding may also extend to a number of other neurological disorders including Fragile X syndrome, the study's authors write. Down syndrome is caused by a trisomy of human chromosome 21, and it remains a challenge to identify the genes on this chromosome responsible for the condition's symptoms. Previous research has shown that a gene encoding Down syndrome cell adhesion molecule (DSCAM) may be responsible for the neuronal defects seen in the disorder, so a team led by scientists from the University of Michigan set out to determine the effects of altered DSCAM levels in mouse models of Down syndrome. They show in the mice that an extra copy of the DSCAM gene causes presynaptic overgrowth of two types of neurons in the neocortex — chandelier cells and basket cells — that play important roles in controlling excitatory neuron output, leading to innervation of neocortical pyramidal neurons. Down syndrome mice with normalized DSCAM levels, meanwhile, did not show these effects. The findings, the researchers state, highlight the role of DSCAM overexpression in Down syndrome and its potential as a pathogenic driver in related neurological disorders.