Deciphering the phenotype-genotype relationships in DS provides a powerful approach to examine pathogenesis. Efforts to enhance cognition, via studies to decipher the genes and mechanisms responsible for cognitive deficits, are a high priority. Toward this goal, we and others pursue an additive/subtractive approach in mouse genetic models of DS. Studies have documented dose effects for a number of specific genes. A role for increased dosage of APP in the pathogenesis of the Alzheimer’s disease in DS is now supported by studies in both mouse models and humans (Head et al., 2016; Lott et al., 2006; Prasher et al., 1998; Salehi et al., 2006). We observed that an extra copy of App contributed to compromised retrograde axonal transport of NGF and degeneration of cholinergic neurons in Ts65Dn mice (Salehi et al., 2006). Triplication of synaptojanin 1 (Synj1), the protein product of which has been shown to regulate clathrin-mediated endocytosis, leads to the enlargement of early endosomes (Cossec et al., 2012). Transgenic mice harboring 4–5 copies of the human SOD1 gene showed an increase in GABAergic inhibition and diminished LTP in the
