Molecular basis of pharmacotherapies for cognition in Down syndrome

Abstract

Intellectual disability in Down syndrome (DS) ranges from low normal to severely impaired and has a significant impact on the quality-of-life of the individuals affected and their families. Because the incidence of DS remains at approximately 1 in 700 live births and the lifespan is now >50 years, development of pharmacotherapies for cognitive deficits is an important goal. DS is due to an extra copy of human chromosome 21 and has often been considered too complex a genetic abnormality to be amenable to intervention. However, recent successes in rescuing learning/memory impairments in a mouse model of DS suggest that this negative outlook may not be justified. In this contribution, we first review the DS phenotype, chromosome 21 gene content and mouse models. We then discuss recent successes and the remaining challenges in the identification of targets for and preclinical evaluation of potential therapeutics.

Figure 1. HSA21q RefSeqP gene distribution in the major mouse models of DS

A schematic of HSA21q is shown at the left. Schematics of the orthologous segments of MMU10, 17 and 16, and of the trisomic regions of the major mouse models of DS are shown approximately to scale [13-17]. Dashed horizontal lines indicate regions of HSA21q defined by the differing trisomic segments in MMU16 models. Numbers refer to RefSeqP genes within each region. Locations of representative RefSeqP genes are indicated [8,9,18].