416 - Neural basis of locomotor dysfunction in the Ts65Dn model of Down syndrome

Poster Number: 416
Publication Number: 416.237

Aaron Sathyanesan, Children's National Health System, Washington, DC, United States; Panagiotis Kratimenos, Children's National Hospital, Washington, DC, United States; Vittorio Gallo, Children's National Health System, Washington, DC, United States

Background: Down syndrome (DS) affects a range of behavioral domains in children including motor and cognitive function. While atypical cognitive processing has been well studied in DS, locomotor dysfunction is relatively understudied. Cerebellar pathology has been consistently observed in DS, and is thought to contribute to motor dysfunction. Pre-clinical animal model studies of DS have indicated atypical cerebellar function. However, these studies have used paradigms that are not cerebellum-specific. Consequently, the specific cerebellar pathways underlying locomotor learning that are disrupted in DS remain poorly understood.

Objective: The goal of this work is to identify specific cerebellar circuit alterations that result in locomotor dysfunction in the Ts65Dn mouse model of DS.

Design/Methods: We used automated behavioral quantification using the ErasmusLadder to measure locomotor coordination and cerebellar adaptive learning, cellular analysis of synaptic deficits in the cerebellar cortex, and sterotaxic injection of neuronal activity indicators into the cerebella of Ts65Dn animals to enable functional characterization during behavior.

Results: Behavioral data for young Ts65Dn animals indicated significant locomotor performance deficits as well as cerebellum-dependent adaptive learning deficits. Analysis indicated differences in locomotor stepping patterns in the Ts65Dn group compared to euploid littermates. Ts65Dn animals also make a significantly larger number of missteps compared to controls. Importantly, during learning sessions, Ts65Dn animals have significantly higher post-perturbation steptimes, indicative of significant adaptive cerebellum-dependent learning deficits. Cellular analysis suggests a sustained delay in climbing fiber-to-Purkinje cell synapse formation across development. Finally, in order to quantify Purkinje cell function in Ts65Dn nimals, we employed a combinatorial adenoviral-associated strategy. Using this strategy, we have successfully obtained specific expression of GCaMP6f in Purkinje cells in order to quantify functional deficits during locomotor behavioral task performance on the ErasmusLadder.Conclusion(s): Our behavioral and cellular analysis data indicate a strong link between alterations in cerebellar circuitry and locomotor dysfunction in the Ts65Dn model of DS. In addition, our in vivo analysis using fiber photometry will provide a platform to systematically analyze the underlying circuit dysfunction in the Ts65Dn model. This will deepen our mechanistic understanding of neurological deficits in DS and provide a platformto develop targeted circuit-based therapeutic agents.