Trisomy 21 Alters Motor Coordination, Vocal Communication, and Cerebellar Circuit Connectivity in the TcMAC21 Mouse.

Individuals with Down syndrome (DS) frequently face challenges with motor control and coordination, affecting their daily physical movements. Speech and language difficulties are also well-documented in DS, but the degree to which these challenges relate to underlying motor coordination deficits remains poorly understood. Using a DS mouse model containing triplication of a nearly complete human chromosome 21, the TcMAC21 mouse, we identified cerebellar circuit dysfunction as a convergent mechanism for both motor and linguistic impairments. Systematic analysis revealed disrupted Purkinje cell organization throughout development, accompanied by specific deficits in cerebellar-dependent behaviors including motor learning, vocalization, and maternal care. Structural measurements and targeting by cell-specific DREADDs uncovered disrupted calcium homeostasis in Purkinje neurons during critical periods of climbing fiber refinement as one contributing factor. In vivo neurophysiological recording in TcMAC21 mice revealed reduced cerebello-thalamic synchrony during locomotor activity. These findings identify calcium signaling as a key developmental pathway linking chromosomal trisomy to cerebellar circuit dysfunction, providing a novel framework for understanding both motor and linguistic deficits in DS that extends beyond traditional cortico-centric models.