Activation of extracellular signal-regulated kinase signaling by chronic electroconvulsive shock in the rat frontal cortex.

The effects of chronic electroconvulsive shock (ECS), given daily for 1, 5 and 10 days, on the activation of extracellular signal-regulated kinase (ERK) were studied in the rat frontal cortex. The phosphorylation of MEK1/2 and ERK1/2 increased through 5 days of ECS. Thereafter, a plateau was achieved. The expression of brain-derived neurotrophic factor was continuously increased for 10 days. Our data show that the effect of ECS on ERK1/2 signaling is increased with chronic treatment.

Transient activation of protein phosphatase 2A induced by electroconvulsive shock in the rat frontal cortex.

We have attempted to determine the effects of electroconvulsive shock (ECS) on protein phosphatase 2A (PP2A) in the frontal cortices of rats. PP2A exhibited a 30% increase in activity immediately after ECS treatment. Immunoblot analysis revealed that phosphorylation signals, including protein kinase B (Akt/PKB), glycogen synthase kinase-3beta (GSK-3beta), and cyclic adenosine monophosphate response element binding protein (CREB) were reduced immediately after ECS treatment. When an additional ECS was administered after the activation of these kinases, the immediate reactivation of PP2A overrode the kinase activity. ECS induces transient PP2A activation prior to kinase activation, and this pattern of activity may induce the biphasic phosphorylation of substrate proteins.

Region-specific phosphorylation of ERK5-MEF2C in the rat frontal cortex and hippocampus after electroconvulsive shock.

ERK5-MEF2C has been implicated in many aspects of neuronal survival and neuroprotection. Neurotrophic effects have been considered as one of the mechanisms in therapeutic electroconvulsive shock (ECS). To investigate whether ECS activates ERK5-MEF2C, we examined the phosphorylation of ERK5, along with its downstream molecule MEF2C, after ECS in the rat frontal cortex and hippocampus. Increased phosphorylation of ERK5 was observed immediately after ECS, but was barely detectable from 2 min after ECS in both the frontal cortex and the hippocampus. The level of MEF2C phosphorylation was decreased immediately after ECS in both regions. It was increased from 2 min and maintained until 10 min after ECS in the frontal cortex, but it returned to the basal level from 2 min after ECS in the hippocampus. Taken together, these results suggest that ECS can regulate the region-specific activity of ERK5-MEF2C pathways in the rat brain.

Region-specific phosphorylation of ATF-2, Elk-1 and c-Jun in rat hippocampus and cerebellum after electroconvulsive shock.

There have been reports of regional differences in the activation of mitogen activated protein kinases (MAPKs) and in the induction of immediate early genes after electroconvulsive shock (ECS) in the rat brain. This study was performed to determine whether ECS induce the region-specific phosphorylation of MAPK-downstream transcription factors, ATF-2, Elk-1, c-Jun, in rat hippocampus and cerebellum. Following ECS, the phosphorylation of ATF-2 was highly increased in the hippocampus but slightly in the cerebellum. The phosphorylation of Elk-1 was increased in the cerebellum but not in the hippocampus. In contrast, the phosphorylation of c-Jun was increased only in the hippocampus. These results indicate that ECS can induce the region-specific phosphorylation of MAPK-downstream transcription factors in rat hippocampus and cerebellum.

Electroconvulsive shock increases the phosphorylation of amphiphysin II in the rat cerebellum.

Amphiphysin II (Amph2) is known to undergo rapid dephosphorylation and phosphorylation at nerve terminals. After in vivo electroconvulsive shock (ECS) in the rat cerebellum, we found an electrophoretic mobility retardation of Amph2, which suggested an increased degree of phosphorylation above the non-stimulated level. This shifted signal was observed from 1 min, reached the maximum level at 5 min and extended beyond 2 h after ECS. The shifted band was markedly decreased by the phosphatase treatment. Pretreatment with cyclosporin A augmented the mobility retardation of Amph2 after ECS. Our results indicate that ECS induces the phosphorylation of Amph2 in the rat cerebellum.

Differential regulation of FAK and PYK2 tyrosine phosphorylation after electroconvulsive shock in the rat brain.

It has been suggested that FAK and PYK2 have differential regulatory pathways and differential functions in the central nervous system. The authors have previously reported that electroconvulsive shock (ECS) activates PYK2 mediated signaling in the rat hippocampus. In the present article, the authors examined the effect of ECS on PYK2 and FAK mediated signaling in the rat cerebral cortex and hippocampus. Our results showed that ECS activated PYK2 more preferentially than FAK in both the cortex and the hippocampus. The association of Src-family kinases with FAK and PYK2 was also distinctively affected by ECS; Src was mainly associated with PYK2 while Yes was associated with FAK. The phosphorylation of FAK and PYK2 at the key tyrosine residue was not well correlated with the association with Src-family kinases.

Effects of MK-801 and electroconvulsive shock on c-Fos expression in the rat hippocampus and frontal cortex.

Both the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and electroconvulsive shock (ECS) have been reported to induce c-Fos in rat brain. However, the former has anticonvulsant and psychotomimetic effects and the latter has proconvulsant and antipsychotic effects. To understand the mode of action of these treatments, the authors examined the effect of MK-801 and the interaction between MK-801 and ECS on the induction of c-Fos in the rat hippocampus and frontal cortex. MK-801 induced c-Fos in these brain regions in a nonlinear dose-response relationship. Maximum effect was achieved with 1-2 mg/kg of MK-801. The level of c-Fos paralleled animal hyperkinetic behavior, suggesting the role of c-Fos in the induced psychotomimetic behaviors. Pretreatment with MK-801 dose-dependently attenuated both the seizures and c-Fos expression by ECS. However, at an MK-801 pretreatment dose of 8 mg/kg, which completely blocked ECS-induced seizure, the induction of c-Fos was not completely blocked, suggesting non-NMDA mediated pathways of the induction of c-Fos by ECS.

Activation of protein kinase B (Akt) signaling after electroconvulsive shock in the rat hippocampus.

Akt (protein kinase B, PKB) is one of the major downstream pathways of neurotrophin signaling and plays important roles in the cell survival and synaptic plasticity of the central nervous system. Electroconvulsive shock (ECS) has neurotrophic effect and it affects the synaptic plasticity. It can activate another major pathway of neurotrophin signaling, i.e., Ras-Raf-MEK-Erk cascade. In this paper, the authors investigated whether ECS can activate Akt signaling in the rat hippocampus. After a single ECS, the phosphorylation of Akt was increased, as were the signals detected by phospho-PDK1 substrate antibody, which suggests the activation of PDK1, an upstream molecule of Akt. The phosphorylation of downstream molecules of Akt, forkhead transcription factors (FKHR), endothelial nitric oxide synthase (eNOS), and glycogen synthase kinase-3beta (GSK-3beta) was also increased. The increased phosphorylation of Akt appeared within 5 min of ECS and its time frame paralleled that of the phosphorylation of Erks. Taken together, these results suggest that ECS activates Akt signaling over a similar time scale to that of Erks in the rat hippocampus.

Behavioural pharmacology of polygalasaponins indicates potential antipsychotic efficacy.

Polygalasaponins were extracted from a plant (Polygala tenuifolia Willdenow) that has been prescribed for hundreds of years to treat psychotic illnesses in Korean traditional medicine. Previous in vitro binding studies suggested a potential mechanism for its antipsychotic action, as polygalasaponin was shown to have an affinity for both dopamine and serotonin receptors [Psychopharmacol. Bull. 31 (1995) 139.]. In the present study we have investigated the functional in vivo actions of this material in tests that are predictive of dopamine and serotonin antagonist activities. Polygalasaponin (25-500 mg/kg) was shown to produce a dose-related reduction in the apomorphine-induced climbing behaviour (minimum effective dose [ED(min)] 25 mg/kg ip, 250 mg/kg sc and po), the 5-hydroxytryptamine (5-HTP)-induced serotonin syndrome (ED(min) 50 mg/kg ip) and the MK-801-induced hyperactivity (ED(min) 25 mg/kg ip) in mice. This compound also reduced the cocaine-induced hyperactivity (ED(min) 25 mg/kg ip) in rats. These results demonstrated that polygalasaponin has dopamine and serotonin receptor antagonist properties in vivo. This might suggest its possible utility as an antipsychotic agent.

Associations between DRDs and schizophrenia in a Korean population: multi-stage association analyses.

The dysregulation of the dopaminergic system has been implicated in the pathophysiology of major psychosis, including schizophrenia, with dopamine receptor genes (DRDs) presently targeted as the most promising candidate genes. We investigated DRD1-5 for association with schizophrenia using a multi-stage approach in a Korean sample. One hundred forty-two SNPs in DRD1-5 were selected from the dbSNP, and the associations of each SNP were then screened and typed by MALDI-TOF mass spectrometry using pooled DNA samples from 150 patients with major psychosis and 150 controls. Each of the suggested SNPs was then genotyped and tested for an association within the individual samples comprising each pool. Finally, the positively associated SNPs were genotyped in an extended sample of 270 patients with schizophrenia and 350 controls. Among the 142 SNPs, 88 (62%) SNPs in our Korean population were polymorphic. At the pooling stage, 10 SNPs (DRD1: 2, DRD2: 3, and DRD4: 5) were identified (P<0.05). SNPs rs1799914 of DRD1 (P=0.046) and rs752306 of DRD4 (P=0.017) had significantly different allele frequencies in the individually genotyped samples comprising the pool. In the final stage, with the extended sample, the suggestive association of DRD4 with rs752306 was lost, but the association of DRD1 with rs1799914 gained greater significance (P=0.017). In these large-scale multi-stage analyses, we were able to find a possible association between DRD1 and schizophrenia. These findings suggested the potential contribution of a multi-step strategy for finding genes related to schizophrenia.

The effect of a periodic absorptive strip arrangement on an interior sound field in a room.

In this paper we study the effect of periodically arranged sound absorptive strips on the mean acoustic potential energy density distribution of a room. The strips are assumed to be attached on the room's surface of interest. In order to determine their effect, the mean acoustic potential energy density variation is evaluated as the function of a ratio of the strip's arrangement period to wavelength. The evaluation demonstrates that the mean acoustic potential energy density tends to converge. In addition, a comparison with a case in which absorptive materials completely cover the selected absorptive plane shows that a periodic arrangement that uses only half of the absorptive material can be more efficient than a total covering, unless the frequency of interest does not coincide with the room's resonant frequencies. Consequently, the results prove that the ratio of the arrangement period to the wavelength plays an important role in the effectiveness of a periodic absorptive strip arrangement to minimize a room's mean acoustic potential energy density.