A. Drago, Naples G. Erdmann, Berlin A. Fischer, Göttingen J.M. Ford, San Francisco, Calif. S. Galderisi, Naples M. Hatzinger, Solothurn U. Hegerl, Leipzig K. Hirata, Mibu M. Kato, Osaka J. Kornhuber, Erlangen D. Lehmann, Zürich P. Monteleone, Naples G. Okugawa, Osaka G.N. Papadimitriou, Athens M. Popoli, Milano M. Reuter, Bonn F. Rösler, Marburg G. Ruigt, Oss J.K. Rybakowski, Poznan F. Schneider, Aachen R. Schwarting, Marburg M. Shigeta, Tokyo D. Souery, Brussels A. Steiger, Munich P. Willner, Swansea Associate Editors

The AKT1 gene has been associated with the genetic aetiology of schizophrenia. Following the overlap model of bipolar disorder and schizophrenia, we aimed to investigate AKT1 genetic variants and protein expression in both diseases. A total of 679 subjects with European ancestry were included: 384 with schizophrenia, 130 with bipolar disorder and 165 controls. Six single nucleotide polymorphisms (SNPs) were investigated for association with the diseases using single‐ and multi‐locus analyses. AKT1 and AKT2 protein levels were measured in post‐mortem brain tissues from ante‐mortem diagnosed schizophrenia (n = 30) and bipolar disorder subjects (n = 12) and matched controls. The analysis identified a significant global distortion in schizophrenia (P = 0.0026) and a weak association in bipolar disorder (P = 0.046). A sliding window procedure showed a five‐SNP haplotype (TCGAG) to be associated with schizophrenia (P = 1.22 × 10−4) and bipolar disorder (P = 0.0041) and a four‐SNP haplotype (TCGA) with the combined sample (1.73 × 10−5). On the basis of selected genotypes, a significant difference in protein expression emerged between subjects (P < 0.02). In conclusion, our findings, by showing the involvement of the AKT1 gene in both schizophrenia and bipolar disorder, support the role of AKT1 in the genetics of both disorders and add support to the view that there is some genetic overlap between them.

ObjectivesMajor depression disorder (MDD) is still a major public health problem and the understading of its neurobiology is still poor. We are interested in the impairment of the neuroplasticity, as hypothesis. Evidence suggest that Akt/GSK3ß axis plays a role mediating hormones actions in neuronal survival. The objective of our study was to assess, in MDD, the regulation of protein and lipid kinases involved in the signaling pathway: PI3K-Akt/PKB-GSK3α/ß-ß-catenin and a phosphatase, PTEN.MethodsDrug-free postmortem brain cortices (VPFC) from antemortem diagnosed depressed subjects, and in few cases, neuroblastoma cells, were used. Applying the methods of western blot, enzymatic activity, we measured the activities, the levels of several proteins and their expression: Akt1 ; GSK3ß ; pGSK3ß ; PI3K ; PTEN ; ß-catenin. Statistical significance was set at p< 0.05.ResultsWith respect to control subjects, the main changes observed in MDD can be summarized as follow : The PI3K enzymatic activity was decreased without changes in protein levels. The GSK3ß activity was increased, but the total activity (α+ß isoforms) was not changed, nor were the total GSKαβ protein levels. The Akt1 activity was decreased, The PTEN protein levels were decreased. The ß catenin levels and the tGSK3ß-to-pGSK3 ratio were altered.ConclusionsThe data show a major depression-associated blunting of the PI3K-Akt-GSK3 signaling pathway. The study of protein and lipid kinases and phosphatases is particularly relevant because of crucial roles played by these proteins in neuron survival, proliferation and apoptosis. It adds further support to the neuroplastic hypothesis of affective disorder.

Schizophrenia (SCZ) afflicts around 1% of the world’s population with characteristic symptoms such as hallucinations, delusions, and cognitive disorders. Several experimental studies in the past have indicted brain histaminergic neuronal system involvement in the pathogenesis of psychotic disorders including SCZ. Present study investigates anti-schizophrenic activity using two histamine H3-receptor (H3R)-antagonists/inverse agonists, ciproxifan (3.0 mg/kg, ip) and clobenpropit (15 mg/kg, ip), on some of the established animal model of schizophrenia, for example, amphetamine (AMPH) and dizocilpine (MK-801)-induced hyperactivity, apo-morphine (APO)-induced climbing behavior, scopolamine and MK-801-induced learning and memory deficits and haloperidol-induced catalepsy including determination of acetylcholinesterase (AChE) activity. Results of the present study demonstrate that ciproxifan and clobenpropit were able to control AMPH and MK-801-induced hyperlocomotor activities demonstrated as reduced horizontal activity and reduced number of movements made by rats. Further, there was overall reduction in APO-induced climbing behavior. Learning and memory deficits, as evaluated on elevated plus maze, followed by estimation of brain AChE activity demonstrated positive results with these protypical imidazole H3R-antagonists/inverse agonists.In conclusion, present study demonstrates anti-schizophrenic like activities of ciproxifan and clobenpropit and supports the therapeutic interest of histamine H3R antagonists/inverse agonists to improve symptomatic treatment of psychotic disorders.