Forebrain Shh overexpression improves cognitive function in a Down syndrome mouse model and euploid littermates

People with Down syndrome (DS) have intellectual disability, early-onset dementia, and cerebellar hypoplasia. Trisomic cerebellar granule cell precursors from Ts65Dn, a mouse model of DS, had a deficit in mitogenic response to Sonic hedgehog (Shh) in vitro, and newborn Ts65Dn mice received a single subcutaneous injection of the Shh signaling agonist SAG had normalized cerebellar morphology and improved spatial learning and hippocampal synaptic plasticity at adult. However, cognitive effects of Shh overexpression in vivo and where SAG acts to improve cognitive outcomes of trisomy are unknown. Here, we created an inducible human Shh (hShh) knock-in mouse, TRE-bi-hShh-Zsgreen1 (TRE-hShh), expressing dually-lipidated Shh-Np in the presence of transactivator (tTA). Double transgenic mice, Camk2a-tTA;TRE-hShh (Camk2a-hShh) and Pcp2-tTA;TRE-hShh (Pcp2-hShh), increased Shh signaling in forebrain and cerebellum, respectively. Forebrain Shh overexpression normalized hyperactivity, and spatial learning and memory deficits in 3-month-old Ts65Dn, while Shh overexpression in cerebellum had no effect. Further, Camk2a-hShh delayed early-onset severe cognitive impairment in 7-month-old Ts65Dn and enhanced spatial cognition in euploid (Eu) and showed no effect on the longevity of Eu or Ts65Dn, and MRI demonstrated that Pcp2-hShh mitigated disproportionately small cerebellum in Ts65Dn. Finally, Ts65Dn at postnatal day 6 had reduced Gli1 levels in hippocampus and cerebellum, which could be at least partially rescued by Camk2a-hShh and Pcp2-hShh, respectively. Our findings suggest restoration of impaired Shh signaling in forebrain from the perinatal and early postnatal period improves cognitive function.