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The mechanistic target of rapamycin (mTOR)-signaling and dihydropyrimidinase-like 2 (DPYSL2), which are increasingly gaining attention as potential therapeutic targets for schizophrenia, are connected via Cap-dependent translation of the 5'TOP motif. We quantified the expression of molecules constituting the mTOR-signaling and DPYSL2 in the prefrontal cortex (PFC) and superior temporal gyrus (STG) of postmortem brain tissue samples from 24 patients with schizophrenia and 32 control individuals and conducted association analysis to examine abnormal regulation of DPYSL2 expression by the mTOR-signaling in schizophrenia. The average ribosomal protein S6 (S6) levels in the PFC and STG were lower in patients with schizophrenia (p < 0.01). DPYSL2 expression showed a significant positive correlation with phospho-S6 expression levels, which were effectors of mTOR translational regulation, and the correlation slope between phospho-S6 and DPYSL2 expressions differed between cases and controls. Association analyses of these mTOR-signaling and DPYSL2 alterations with genetic polymorphisms and the clinical profile suggested that certain genetic variants of DPYSL2 require high mTOR-signaling activity. Thus, the findings confirmed decreased S6 expression levels in schizophrenia and supported the relationship between the mTOR-signaling and DPYSL2 via 5'TOP Cap-dependent translation, thus providing insights connecting the two major schizophrenia treatment strategies associated with the mTOR-signaling and DPYSL2.

Parkinson's disease is often complicated by psychiatric symptoms. Psychiatrists are caught in a dilemma between such symptoms and physical treatment since Parkinson's disease sometimes shows treatment resistance based on pharmacological treatment-induced dopamine dysfunction. Here, we report on a 64-year-old woman with a 15-year history of Parkinson's disease with stage IV severity based on the Hoehn and Yahr scale. She was admitted to our hospital with a diagnosis of major depressive disorder with psychotic features. Unfortunately, her treatment course for depression was complicated by neuroleptic malignant syndrome. Because we were concerned about the persistence of her depressive symptoms, the risk of psychotropic drugs causing adverse effects, and progressive disuse syndrome, we administered modified electroconvulsive therapy. Her symptoms of neuroleptic malignant syndrome and depression sufficiently improved after five sessions of modified electroconvulsive therapy. Additionally, the primary motor symptoms of her Parkinson's disease also markedly improved. The improvement of neuroleptic malignant syndrome and her motor symptoms based on dopamine dysfunction can be explained by electroconvulsive therapy's effectiveness in activating dopamine neurotransmission. Besides, the marked improvement of her depressive episode with psychotic features was presumed to involve dopamine receptor activation and regulation. Because advanced Parkinson's disease can sometimes be refractory to treatment based on pharmacological treatment-induced dopamine dysfunction, psychiatrists often have difficulty treating psychiatric symptoms; electroconvulsive therapy may stabilize the dopaminergic system in such cases, presenting a possible non-pharmacologic treatment option for Parkinson's disease.

The family of epidermal growth factor (EGF) including neuregulin-1 are implicated in the neuropathology of schizophrenia. We established a rat model of schizophrenia by exposing perinatal rats to EGF and reported that the auditory pathophysiological traits of this model such as prepulse inhibition, auditory steady-state response, and mismatch negativity are relevant to those of schizophrenia. We assessed the activation status of the auditory cortex in this model, as well as that in patients with schizophrenia, by monitoring the three neural activity-induced proteins: EGR1 (zif268), c-fos, and Arc. Among the activity markers, protein levels of EGR1 were significantly higher at the adult stage in EGF model rats than those in control rats. The group difference was observed despite an EGF model rat and a control rat being housed together, ruling out the contribution of rat vocalization effects. These changes in EGR1 levels were seen to be specific to the auditory cortex of this model. The increase in EGR1 levels were detectable at the juvenile stage and continued until old ages but displayed a peak immediately after puberty, whereas c-fos and Arc levels were nearly indistinguishable between groups at all ages with an exception of Arc decrease at the juvenile stage. A similar increase in EGR1 levels was observed in the postmortem superior temporal cortex of patients with schizophrenia. The commonality of the EGR1 increase indicates that the EGR1 elevation in the auditory cortex might be one of the molecular signatures of this animal model and schizophrenia associating with hallucination.

Description, High-sugar diet in adolescence induces neural angiopathy and multiple psychiatric endophenotypes with impaired glucose logistics., Metabolic dysfunction is thought to contribute to the severity of psychiatric disorders; however, it has been unclear whether current high–simple sugar diets contribute to pathogenesis of these diseases. Here, we demonstrate that a high-sucrose diet during adolescence induces psychosis-related behavioral endophenotypes, including hyperactivity, poor working memory, impaired sensory gating, and disrupted interneuron function in mice deficient for glyoxalase-1 (GLO1), an enzyme involved in detoxification of sucrose metabolites. Furthermore, the high-sucrose diet induced microcapillary impairments and reduced brain glucose uptake in brains of Glo1-deficient mice. Aspirin protected against this angiopathy, enhancing brain glucose uptake and preventing abnormal behavioral phenotypes. Similar vascular damage to our model mice was found in the brains of randomly collected schizophrenia and bipolar disorder patients, suggesting that psychiatric disorders are associated with angiopathy in the brain caused by various environmental stresses, including metabolic stress.

Phosphoinositides (PIs) play important roles in the structure and function of the brain. Associations between PIs and the pathophysiology of schizophrenia have been studied. However, the significance of the PI metabolic pathway in the pathology of schizophrenia is unknown. We examined the expression of PI signaling-associated proteins in the postmortem brain of schizophrenia patients. Protein expression levels of phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5K1C), phosphatidylinositol 4-kinase alpha (PIK4CA, also known as PIK4A), phosphatase and tensin homolog deleted from chromosome 10 (PTEN), protein kinase B (Akt), and glycogen synthase kinase 3β (GSK3β) were measured using enzyme-linked immunosorbent assays and multiplex fluorescent bead-based immunoassays of the prefrontal cortex (PFC) of postmortem samples from 23 schizophrenia patients and 47 normal controls. We also examined the association between PIK4CA expression and its genetic variants in the same brain samples. PIK4CA expression was lower, whereas Akt expression was higher, in the PFC of schizophrenia patients than in that of controls, PIP5K1C, PTEN, and GSK3β expression was not different. No single-nucleotide polymorphism significantly affected protein expression. We identified molecules involved in the pathology of schizophrenia via this lipid metabolic pathway. These results suggest that PIK4CA is involved in the mechanism underlying the pathogenesis of schizophrenia and is a potential novel therapeutic target.

Metabolic dysfunction is thought to contribute to the severity of psychiatric disorders; however, it has been unclear whether current high-simple-sugar diets contribute to pathogenesis of these diseases. Here we demonstrate that a high-sucrose diet during adolescence induces psychosis-related behavioral endophenotypes, including hyperactivity, poor working memory, impaired sensory gating, and disrupted interneuron function in mice deficient for glyoxalase-1 (Glo1), an enzyme involved in detoxification of sucrose metabolites. Further, the high-sucrose diet induced microcapillary impairments and reduced brain glucose uptake in brains of Glo1 deficient mice. Aspirin protected against this angiopathy, enhancing brain glucose uptake, and preventing abnormal behavioral phenotypes. Similar vascular damage to our model mice was found in the brains of randomly collected schizophrenia and bipolar disorder patients, suggesting that psychiatric disorders are associated with angiopathy in the brain caused by various environmental stresses, including metabolic stress.

Background The molecular mechanisms underlying schizophrenia remain largely unclear, and we recently identified multiple proteins significantly altered in the postmortem prefrontal cortex (PFC) of schizophrenia patients amongst which aldehyde dehydrogenase 4 family member A1 (ALDH4A1) was especially elevated. In this study, we aimed to investigate the expression of ALDH4A1 in the PFC and superior temporal gyrus (STG) and to elucidate functional correlations between schizophrenia risk alleles and molecular expression profiles in the postmortem brains of patients with schizophrenia. Methods The levels of ALDH4A1 protein expression in the PFC and STG in postmortem brains from 24 patients with schizophrenia, 8 patients with bipolar disorder, and 32 controls were assessed using enzyme-linked immunosorbent assay. Moreover, we explored the associations between ALDH4A1 expression and genetic variants in enzymes associated with proline metabolism, including ALDH4A1 (schizophrenia [n = 22], bipolar disorder [n = 6], controls [n = 11]). Results ALDH4A1 levels were significantly elevated in both the PFC and STG in patients with schizophrenia and tended to elevate in patients with bipolar disorder. Furthermore, ALDH4A1 expression levels in the PFC were significantly associated with the following three single-nucleotide polymorphisms: rs10882639, rs33823, rs153508. We also found partial coexpression of ALDH4A1 in mitochondria in a subset of putative astrocytes of postmortem brain. Limitations Our study population was relatively small, particularly for a genetic study. Conclusion These findings indicate that altered expression of ALDH4A1 may reflect the potential molecular mechanisms underlying the pathogenesis of schizophrenia and bipolar disorder, and may aid in the development of novel drug therapies.