Hyperactivation of MEK1 in cortical glutamatergic neurons results in projection axon deficits and aberrant motor learning

Abnormal Extracellular Regulated Kinase 1/2 (ERK1/2) signaling is linked to multiple neurodevelopmental diseases, especially the RASopathies, which typically exhibit ERK1/2 hyperactivation in neurons and non-neuronal cells. To better understand how excitatory neuron-autonomous ERK1/2 activity regulates the development of the mouse motor cortex, we conditionally expressed a hyperactive MEK1 S217/221E variant using Nex/NeuroD6:Cre . Our results show that MEK1 S217/221E expression led to persistent hyperactivation of ERK1/2 in neocortical axons, but not excitatory neuron somas or nuclei. We noted reduced axonal arborization of multiple subcortical target domains in mutants and reduced cortical expression of the activity dependent gene, ARC. These changes did not coincide with significant differences in voluntary locomotor activity or motor performance in the accelerating rotarod task. However, motor learning in a single-pellet retrieval task was significantly diminished in Nex/NeuroD6:Cre ; MEK1 S217/221E mutants. Restriction of MEK1 S217/221E expression to layer V cortical neurons recapitulated axonal outgrowth deficits, however, had no effect on motor learning. Collectively, these results indicate that within the cortex, glutamatergic neuron-autonomous hyperactivation of MEK1 is sufficient to drive deficits in axon outgrowth, activity dependent gene expression, and skilled motor learning. Summary statement MEK-ERK1/2 hyperactivation in developing cortical excitatory neurons is sufficient to decrease long-range axonal outgrowth, which coincides with reduced Arc expression and deficits in aspects of skilled motor learning by adulthood.