Human cortical development and neural plasticity altered by trisomy 21

ABSTRACT
Down syndrome (DS, trisomy 21, T21), a complex multigene disorder and the most common genetic cause of
intellectual disability. However, surprisingly little is known about the underlying mechanisms that lead to cognitive
impairment in DS. There are fewer neurons in adult DS cortex and reduced neurogenesis and synaptogenesis
have been implicated as features of DS development. Yet, what and how specific neurons and synaptic contacts
are affected at which period of development and what molecular pathways underlie these defects that lead to
intellectual disability remain unclear. We propose to build models based on human induced pluripotent stem cells
(iPSCs), to interrogate how T21 disrupts developmental processes in DS. To ensure the validity of the stem cell
based models, we will first establish a cellular, synaptic, and molecular atlas of the DS prenatal cortex. By
integrating molecular signatures of single cells with the cellular changes both in vivo and in in vitro models, we
will tease out the molecular pathways that are disrupted by T21 that account for the altered neural development.
The results from these experiments will provide mechanistic understanding of intellectual disability in DS. More
broadly, the results will address gaps in our understanding of human cortical neuron development and
consequences of mistakes.

Grant Number: 5R01HD106197-03
NIH Institute/Center: NIH
Principal Investigator: ANITA BHATTACHARYYA