# Altered motor coordination, vocal communication, and cerebellar circuit connectivity in mice carrying a near-complete human chromosome 21

## TL;DR

This study shows that mice with an extra human chromosome 21 exhibit motor and coordination issues linked to cerebellar dysfunction, offering new insights into Down syndrome.

## Contribution

The study identifies cerebellar circuit dysfunction and calcium signaling as key contributors to motor deficits in Down syndrome.

## Key findings

- TcMAC21 mice show disrupted Purkinje neuron organization and hypertrophied climbing fiber synapses.
- Cerebellar nuclear activity is decoupled from locomotion, and cerebello-thalamic synchrony is reduced in TcMAC21 mice.
- Elevated calcium in Purkinje neurons replicates motor and climbing fiber deficits seen in the model.

## Abstract

Individuals with Down syndrome (DS) frequently face challenges with motor control and coordination, affecting their daily physical movements. The neural mechanism underlying motor coordination deficits in DS remains poorly understood. Using the TcMAC21 mice, which carry an extra nearly complete human chromosome 21 in addition to two copies of mouse orthologs, we characterized altered motor function and identified cerebellar circuit dysfunction underlying motor adaptation deficits. We also revealed disrupted Purkinje neuron organization and hypertrophied synapses from climbing fiber afferents, accompanied by specific deficits in cerebellar-dependent behaviors, including motor learning, vocalizations, and maternal care. In vivo calcium recordings showed stochastic decoupling of cerebellar nuclear activity from locomotion states, while cerebello-thalamic synchrony was reduced. Selective elevation of intracellular calcium in developing Purkinje neurons recapitulates motor adaptation deficits and climbing fiber phenotype observed in the TcMAC21 model, supporting the conclusion that cell-autonomous calcium signaling is a functionally relevant feature. This study provides a framework for understanding both motor and cerebellar deficits in DS, extending beyond cortico-centric models.