Extended Data Fig. 7: Proposed model for circuit dysfunctions during delayed motor learning in 16p11.2^+/− mice.

Left: motor learning induces circuit reorganizations in the motor cortex through a multi-step process: In WT mice, during the initial phase of learning, RE neurons explore learning-related activity patterns, and nascent spines are formed to create structural substrates for the new motor memory (1). As learning progresses, NA is being released and ‘task-related’ RE-active neurons refine learning-related activity patterns (2). The refinement process to generate learned movement leads to the elimination of unnecessary spines to achieve proper circuit reorganization (3). Right: in the 16p11.2^+/− mice, the process of circuit reorganization is delayed. The low levels of NA in the motor cortex of 16p11.2^+/− mice could alter the baseline excitability of neurons. Hence, during an RE in the initial phase of learning, ‘task-related’ RE-active neurons become highly active, which leads to elevated ensemble synchrony but learning-induced spine formation is not affected (1). As learning progresses, NA is being released, and neuronal excitability reverts to baseline levels. As the ensemble begins to desynchronize (2), it allows ‘task-related’ RE-active neurons to refine learning-related activity patterns (3). However, the extra step of lowering neuronal activity and desynchronization delays the circuit’s ability to refine activity patterns and eliminate unnecessary spines to achieve proper circuit reorganization (4); thereby causing the delayed motor learning.