Electroconvulsive Seizures Increase the Expression of MAP Kinase Phosphatases in Limbic Regions of Rat Brain

Abstract

The mitogen-activated protein (MAP) kinase cascades regulate a variety of cellular activities, including cell growth, proliferation, and apoptosis, and are reported to play a role in the actions of antidepressant treatment. There are a number of different classes of protein phosphatases that could influence the MAP kinase cascade. One of these, the MAP kinase phosphatase (MKP) family, is known to play a key role in dephosphorylation of activated MAP kinase. In the present study, we analyzed the expression of the MKP1, MKP2, and MKP3 isoforms in rat brain after electroconvulsive seizure (ECS), considered the most effective treatment for depression. In situ hybridization analysis demonstrates that ECS differentially regulates the expression of the MKP isoforms. Expression of MKP1 mRNA is robustly increased by acute ECS in the major cell layers of the hippocampus, including the dentate gyrus granule cell layer and the CA1 and CA3 pyramidal cell layers. In contrast, MKP2 is induced mainly in the dentate gyrus and MKP3 is preferentially increased in the CA1 and CA3 cell layers. In the prefrontal cortex, all three MKP isoforms are upregulated by acute ECS administration. Chronic ECS resulted in a similar pattern of induction for each of the MKP subtypes, demonstrating that there is little or no desensitization of the response to repeated ECS. The induction of MKP expression serves as negative feedback control for the MAP kinase cascades. Upregulation of MKP expression could dampen the actions of ECS, indicating that blockade of the MKPs could enhance the actions of antidepressant treatment.

Regulation of Activin mRNA and Smad2 Phosphorylation by Antidepressant Treatment in the Rat Brain: Effects in Behavioral Models

“…All animals consumed approximately the same amount of the drug-drinking water solution, and there was no difference in fluid intake among the treatment groups. In a previous study using this paradigm, drug levels were determined to be between 100 and 150 ng/ml plasma, which is in the range of drug levels achieved in patients (Kodama et al, 2005). Animals were decapitated on day 21, and brains were removed and frozen immediately for in situ hybridization or the frontal cortex and hippocampus were dissected for protein to be analyzed by Western blot.…”

“…For chronic treatment, rats were given 10 ECSs and decapitated at 6 h after the last seizure. Drug treatment was administered exactly as described by Kodama et al (2005). Groups of rats were administered either fluoxetine (5 mg ⅐ kg ⅐ d) or desipramine (10 mg ⅐ kg ⅐ d) in the drinking water for 21 d (drugs are readily soluble in water).…”

The association of DUSP6 gene with schizophrenia and bipolar disorder: its possible role in the development of bipolar disorder

“…For example, DUSP6 mRNA increases after electroconvulsive seizure in rat brain. 7 Also, atypical antipsychotics and mood stabilizers stimulate ERK pathway involved in synaptic plasticity and long-term potentiation. 8,9 Moreover, MAPK cascade that includes DUSP6 activation is essential for the regulation of circadian rhythm genes, which is another possible etiology of bipolar disorder.…”

Expression changes in mouse brains following nicotine-induced seizures: the modulation of transcription factor networks

“…Indeed, our experimental model detected significantly up-and downregulated genes that were previously reported as differentially expressed following seizures or nicotine, further demonstrating the strength of this experimental model. For example, the upregulation of Dusp1 and Dusp6 genes described here was also shown following electroconvulsive seizures (43) and kainic acid-induced seizures (9).…”

“…These responses are accompanied by stimulation of the expression of numerous genes. Gene expression changes in the brain following seizure activity were previously investigated using different models of seizure induction, including acute and chronic electroconvulsive seizures (2,16,43,52), amygdaloid kindling seizures (12,48), and kainic acid- (36,67,71), pentylenetetrazol- (26,62), and pilocarpine-induced seizures (5,23). These analyses revealed altered expression of transcription factors and other immediate early genes (2,12,36), followed by expression induction of growth factors (52) and genes involved in stress and immune responses (67), signaling pathways (2), neuronal plasticity, and others (48).…”