The extracellular signal-regulated kinase pathway contributes to the control of behavioral excitement

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Abstract
The extracellular signal-regulated kinase (ERK) pathway mediates neuronal plasticity in the CNS. The mood stabilizers lithium and valproate activate the ERK pathway in prefrontal cortex and hippocampus and potentiate ERK pathway-mediated neurite growth, neuronal survival and hippocampal neurogenesis. Here, we examined the role of the ERK pathway in behavioral plasticity related to facets of bipolar disorder. Mice with ERK1 ablation acquired reduced phosphorylation of RSK1, an ERK substrate, in prefrontal cortex and striatum, but not in hippocampus or cerebellum, indicating the ablation-induced brain region-specific ERK signaling deficits. ERK1 ablation produced a behavioral excitement profile similar to that induced by psychostimulants. The profile is characterized by hyperactivity, enhanced goal-directed activity and increased pleasure-related activity with potential harmful consequence. ERK1-ablated mice were hyperactive in multiple tests and resistant to behavioral despair in the forced swim test. These mice displayed more home-cage voluntary wheel running activities, rearings in a large arena and open-arm visits in an elevated plus maze. Treatments with valproate and olanzapine, but not lithium reduced baseline activities in ERK1-ablated mice. All three treatments attenuated amphetamine-induced hyperactivity in ablated mice. These data indicate a profound involvement of ERK1 signaling in behavioral excitement and in the behavioral action of antimanic agents. The extent to which ERK pathway perturbation contributes to the susceptibility, mood switch mechanism(s) and symptom pathophysiology of bipolar disorder requires further investigation. Whether there is a shared mechanism through which mood stabilizers produce their clinical actions on mood, thought and behavioral symptoms of mania also requires further investigation.