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

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 goaldirected 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.

Total ERK1/2 activity regulates cell proliferation

“…Mice lacking ERK1 display minor phenotypes such as behavioral excitement 67 and abnormal responses to stresses such as resistance to ERK1 and ERK2 are positive regulators of cell proliferation of three isoforms of Ras and three isoforms of Raf which are each orthologous to a single human protein (Fig. 1A).…”

Evidence for the involvement of the kainate receptor subunit GluR6 (GRIK2) in mediating behavioral displays related to behavioral symptoms of mania

“…28,30 Briefly, transparent Plexiglas cylinders, 50 cm high with a diameter of 20 cm, were filled with tap water at 22-24 1C to approximately 25 cm in a way that mice were not able to touch the floor or escape. Individual mice were placed in the water for a 6-min session, and their behavior was videotaped for later analysis.…”

“…28,29 A Plexiglas plus-shaped maze containing two dark and enclosed arms and two open and lit arms, elevated 50 cm above ground, was used to examine anxiety-related behaviors. The arms were 30 Â 5 cm with a 5 Â 5 cm center area, and the walls of the closed arms were 40 cm high.…”

“…28 In brief, a 50 Â 50 cm arena was used for the open-field test. To study spontaneous locomotion, mice were placed in one corner of the arena and their behavior was recorded for 60 min with the Ethovision video tracking system (Noldus, Leesburg, VA, USA) and videotaped.…”

Convergent functional genomics of psychiatric disorders

“…More recent work with it involving brain region-specific manipulation of gene expression has revealed a mixed mood phenotype [Mukherjee et al, 2010]. Other recently described genetically engineered models for manic-like behavior involve manipulation of the genes DAT (dopamine transporter) [Young et al, 2010b], GRIN2A (NMDA receptor subunit 2A) [Taniguchi et al, 2009], HINT1 (protein kinase C interacting protein) [Barbier and Wang, 2009], ERK1 (extracellular signal regulated kinase 1) [Engel et al, 2009], and GRIK2 (metabotropic glutamate receptor 6) [Shaltiel et al, 2008;Malkesman et al, 2010]. Candidates emerging from genome-wide association studies of bipolar disorder (CACNA1C [Dao et al, 2010], ANK3 [Leussis et al, 2012]) were also validated in animal models.…”