Dysregulation of astrocyte-secreted pleiotrophin contributes to neuronal structural and functional deficits in Down syndrome.

Neuronal dendrite patterning and synapse formation are tightly regulated during development to promote proper connectivity. Here, we identify downregulation of pleiotrophin, a secreted molecule enriched in astrocytes, as a major contributor to dendrite and synapse deficits in the Ts65Dn mouse model of Down syndrome (DS). We find overlapping deficits in neuronal dendrites and spines in Ts65Dn mutant and pleiotrophin knockout mice. We show that targeting pleiotrophin overexpression to astrocytes in adult Ts65Dn mice in vivo can rescue dendrite morphology as well as restore spine density, synapse number, and plasticity deficits in the hippocampus. Moreover, pleiotrophin promotes dendrite outgrowth in cultured Ts65Dn neurons through Alk-Akt signaling. Our findings highlight dysregulated astrocyte protein secretion as a contributing factor to DS and identify pleiotrophin as a plasticity-inducing molecule that can be used to promote proper circuit connectivity, importantly, at later stages of development after typical periods of circuit refinement have been completed.