Overexpression of Down Syndrome Cell Adhesion Molecule impairs precise synaptic targeting

Fragile X syndrome is caused by loss of Fragile X Mental Retardation Protein (FMRP), an RNA binding protein that suppresses protein translation. Here, we identified Down Syndrome Cell Adhesion Molecule (Dscam) RNA, a molecule involved in neural development and implicated in Down syndrome, bound to FMRP. Elevated Dscam protein levels in Drosophila FMRP null animals and in animals with three copies of the Dscam gene both produced specific and similar synaptic targeting errors in a hard-wired neural circuit which impaired the animal’s sensory perception. Reducing Dscam levels in FMRP null animals reduced synaptic targeting errors and rescued behavioral responses. Our results demonstrate that excess Dscam protein may be a common molecular mechanism underlying altered neural wiring in major causes of intellectual disability. Down syndrome and Fragile X syndrome are two of the most common causes of intellectual disability 1,2. A hallmark of both of these syndromes is elevated protein expression. In Down syndrome this is a consequence of having three copies of Chromosome 21 and the extraneous expression of the thousands of genes located there. In Fragile X syndrome