Dysregulation of astrocyte-secreted pleiotrophin contributes to neuronal structural and functional phenotypes in Down Syndrome.

Neuronal dendrite structure and synapse formation is tightly regulated during development to promote proper connectivity. Astrocyte-secreted proteins act as guidance and pro-synaptogenic factors, and astrocyte protein secretion is dysregulated in neurodevelopmental disorders with aberrant circuitry. Here we identify down-regulation of the astrocyte-secreted molecule pleiotrophin as a major contributor to neuronal phenotypes in the Ts65Dn mouse model of Down Syndrome. Through histological characterizations of Ts65Dn mutant and pleiotrophin knockout mice, we find overlapping phenotypes in neuronal dendrites, spines and intracortical synapses. By targeting pleiotrophin overexpression to astrocytes in Ts65Dn mutant mice in vivo , we show that pleiotrophin can rescue and/or partially restore these phenotypes, and we further correlate structural changes to improved cognitive function. Our findings identify pleiotrophin as a molecule that can be targeted in Down Syndrome to promote proper circuit connectivity, even at later stages of development after typical periods of circuit refinement have closed.