Molecular Changes in the Sensorimotor Cortex During Learning and Recall: Tracking and Manipulating PKMζ

Abstract

Procedural learning and memories, such as those associated with learning how to ride a bike, are believed to be supported by plasticity and reorganization of the sensorimotor cortex. Several studies utilizing a rodent reaching task, as that used in the current work, have shown that procedural learning is accompanied by enhanced synaptic strength and structural modification in the sensorimotor cortex at distinct layers (e.g. layers II/III and V). However, an investigation that causally links these changes with synaptic molecular machinery and behavior has been elusive. This study aims to fill this gap in our current understanding by tracking changes in task performance as well as layer specific modifications in key molecules, atypical protein kinase M zeta (PKMζ) and postsynaptic density protein 95 (PSD-95), that have been shown necessary for the maintenance of long-term potentiation (LTP) and activity-dependent synapse stabilization respectively. Our results demonstrate that PKMζ levels decrease in S1 during an early pause in learning on day 3, and both PKMζ and PSD-95 peak in S1 and M1 once the performance has reached an asymptote on day 9. Continued daily practice after day 9 is accompanied by sustained higher levels of PKMζ, but not PSD-95. Past this correlation, we utilized genetic and pharmacological methods to causally perturb PKMζ during and after learning. We found results indicating the importance of PKMζ both during learning and in maintaining the procedural memory engram. Taken together, we propose a model integrating PKMζ-dependent LTP and PSD-95-assisted synaptogenesis as the molecular mechanisms to encode and store motor memory traces in sensorimotor cortex.