Hedgehog Agonist Therapy Corrects Structural and Cognitive Deficits in a Down Syndrome Mouse Model

Abstract

Down syndrome (DS) is among the most frequent genetic causes of intellectual disability, and ameliorating this deficit is a major goal in support of people with trisomy 21. The Ts65Dn mouse recapitulates some major brain structural and behavioral phenotypes of DS, including reduced size and cellularity of the cerebellum and learning deficits associated with the hippocampus. We show that a single treatment of newborn mice with the sonic hedgehog pathway agonist, SAG1.1 (SAG), results in normal cerebellar morphology in adults. Further, SAG treatment at birth rescued phenotypes associated with hippocampal deficits that occur in untreated adult Ts65Dn mice. This treatment resulted in behavioral improvements and normalized performance in the Morris Water Maze task for learning and memory. SAG treatment also produced physiological effects and partially rescued both NMDA receptor dependent synaptic plasticity and NMDA/AMPA receptor ratio, physiological measures associated with memory. These outcomes confirm an important role for the hedgehog pathway in cerebellar development and raise the possibility for its direct influence in hippocampal function. The positive results from this approach suggest a possible direction for therapeutic intervention to improve cognitive function for this population.

Size Does Not Always Matter: Ts65Dn Down Syndrome Mice Show Cerebellum-Dependent Motor Learning Deficits that Cannot Be Rescued by Postnatal SAG Treatment

“…However, our finding that baseline motor performance during both optokinetic and vestibular, oculomotor behavior was normal in SAG-treated Ts65Dn mice compared with Vehtreated mice suggests that SAG by itself does not present severe adverse side effects on motor behavior. Moreover, SAG treatment can rescue spatial navigation in Ts65Dn mice, although it does not cause such deficits in euploid controls (Das et al, 2013). Therefore, our data suggest that the biological causes underlying cerebellar learning deficits in DS are multicausal, which is not surprising for a complex genetic condition.…”

“…Despite its positive impact on cerebellar neuroanatomical architecture (Roper et al, 2006;Das et al, 2013), SAG treatment failed to rescue long-term cerebellar-based learning. Our results cannot argue in favor of a positive impact of SAG-treatment on neither acquisition nor consolidation during phase-reversal learning; the outcomes of TsVeh and TsSAG mice were virtually indistinguishable, whereas they significantly diverged from those of controls.…”

“…On the day of birth (P0), each pup in a litter received a subcutaneous injection of 20 l of SAG to a final dose of 20 g/g, or an equal volume of vehicle. For details on the methods for histology, see Das et al (2013) and for impact of SAG on histology of cerebellar granular layer, including that of vestibulocerebellum, see Table 1.…”

“…SAG activity was established by comparison to the amount of gcp proliferation after Shh stimulation (Roper et al, 2006;Das et al, 2013). On the day of birth (P0), each pup in a litter received a subcutaneous injection of 20 l of SAG to a final dose of 20 g/g, or an equal volume of vehicle.…”

“…Reduction of granule cells in Ts65Dn is correlated with reduced mitogenic gcp in trisomic mice compared with euploid (Roper et al, 2006). Indeed, treatment of Ts65Dn mice on the day of birth with the "small agonist of hedgehog pathway 1.1" (SAG) has been shown to restore granule cell precursor mitogenesis and normalize cerebellar morphology in adults (Roper et al, 2006;Das et al, 2013). However, because no consistent, cerebellum-specific functional effect has been documented in Ts65Dn mice, it is unclear whether SAG treatment might relieve Ts65Dn animals from potential deficits in cerebellar motor coordination.…”