UC San Diego

Fine motor behavior and circuit development of the motor cortex is associated with selective structural expansion in networks of functionally related neurons 1. Corticospinal neurons are amongst these that exhibit extensive structural plasticity when subjected to forelimb-specific behavioral tasks where these neurons undergo elaborate enrichment in dendritic boutons and an increase in apical and basilar spine density. In contrast, neighboring neurons not directly engaged in the motor behavior do not display the same structural modifications as a consequence of learning. We wanted to determine what drives this anatomical change on a molecular level. First, we identified the learning transcriptome by isolating C8-projecting corticospinal neurons that were subjected to skilled grasped training and purified mRNA-associated ribosomes. Our RNA sequencing revealed amyloid precursor protein as a functional network hub associated with motor learning. We determined if APP protein is upregulated in response to motor learning. Animals were subjected to either 1-day or 7-days of forelimb-skilled grasp training, motor cortices were isolated, and protein extracted. Western blot analysis indicated that holo APP protein is slightly upregulated in response to learning compared to untrained animals. APP proteolytic fragments showed a more robust upregulation in response to learning, and histology of these animals showed APP localization within layer 5 motor neurons suggesting APP protein plays a role during learning where this protein is proteolytically cleaved in response to this task.