Delayed Motor Learning in a 16p11.2 Deletion Mouse Model of Autism is Rescued by Locus Coeruleus Activation

Children with autism spectrum disorder often exhibit delays in achieving motor developmental milestones such as crawling, walking and speech articulation. However, little is known about the neural mechanisms underlying motor-related deficits. Here, we reveal that mice with a syntenic deletion of the chromosome 16p11.2, a common copy number variation associated with autism spectrum disorder, also exhibit delayed motor learning without showing gross motor deficits. Using in vivo two-photon imaging in awake mice, we find that layer 2/3 excitatory neurons in the motor cortex of adult male 16p11.2-deletion mice show abnormally high activity during the initial phase of learning, and the process of learning-induced spine reorganization is prolonged. Pharmacogenetic activation of locus coeruleus noradrenergic neurons was sufficient to rescue the circuit deficits and the delayed motor learning in these mice. Our results unveil an unanticipated role of noradrenergic neuromodulation in improving the delayed motor learning in 16p11.2-deletion male mice.