Linking proteomic alterations in schizophrenia hippocampus to NMDAr hypofunction in human neurons and oligodendrocytes.

Glutamatergic neurotransmission dysfunction and the early involvement of the hippocampus have been proposed to be important aspects of the pathophysiology of schizophrenia. Here, we performed proteomic analysis of hippocampus postmortem samples from schizophrenia patients as well as neural cells-neurons and oligodendrocytes-treated with MK-801, an NMDA receptor antagonist. There were similarities in processes such as oxidative stress and apoptotic process when comparing hippocampus samples with MK-801-treated neurons, and in proteins synthesis when comparing hippocampus samples with MK-801-treated oligodendrocytes. This reveals that studying the effects of glutamatergic dysfunction in different neural cells can contribute to a better understanding of what it is observed in schizophrenia patients' postmortem brains.

An overview of the human brain myelin proteome and differences associated with schizophrenia.

OBJECTIVES: Disturbances in the myelin sheath drive disruptions in neural transmission and brain connectivity as seen in schizophrenia. Here, the myelin proteome was characterised in schizophrenia patients and healthy controls to visualise differences in proteomic profiles. METHODS: A liquid chromatography tandem mass spectrometry-based shotgun proteomic analysis was performed of a myelin-enriched fraction of postmortem brain samples from schizophrenia patients (n = 12) and mentally healthy controls (n = 8). In silico pathway analyses were performed on the resulting data. RESULTS: The present characterisation of the human myelinome led to the identification of 480 non-redundant proteins, of which 102 proteins are newly annotated to be associated with the myelinome. Levels of 172 of these proteins were altered between schizophrenia patients and controls. These proteins were mainly associated with glial cell differentiation, metabolism/energy, synaptic vesicle function and neurodegeneration. The hub proteins with the highest degree of connectivity in the network included multiple kinases and synaptic vesicle transport proteins. CONCLUSIONS: Together these findings suggest disruptive effects on synaptic activity and therefore neural transmission and connectivity, consistent with the dysconnectivity hypothesis of schizophrenia. Further studies on these proteins may lead to the identification of potential drug targets related to the synaptic dysconnectivity in schizophrenia and other psychiatric and neurodegenerative disorders.

Quantitative Subcellular Proteomics of the Orbitofrontal Cortex of Schizophrenia Patients.

Schizophrenia is a chronic disease characterized by the impairment of mental functions with a marked social dysfunction. A quantitative proteomic approach using iTRAQ labeling and SRM, applied to the characterization of mitochondria (MIT), crude nuclear fraction (NUC), and cytoplasm (CYT), can allow the observation of dynamic changes in cell compartments providing valuable insights concerning schizophrenia physiopathology. Mass spectrometry analyses of the orbitofrontal cortex from 12 schizophrenia patients and 8 healthy controls identified 655 protein groups in the MIT fraction, 1500 in NUC, and 1591 in CYT. We found 166 groups of proteins dysregulated among all enriched cellular fractions. Through the quantitative proteomic analysis, we detect as the main biological pathways those related to calcium and glutamate imbalance, cell signaling disruption of CREB activation, axon guidance, and proteins involved in the activation of NF-kB signaling along with the increase of complement protein C3. Based on our data analysis, we suggest the activation of NF-kB as a possible pathway that links the deregulation of glutamate, calcium, apoptosis, and the activation of the immune system in schizophrenia patients. All MS data are available in the ProteomeXchange Repository under the identifier PXD015356 and PXD014350.

The Nuclear Proteome of White and Gray Matter from Schizophrenia Postmortem Brains.

Schizophrenia (SCZ) is a serious neuropsychiatric disorder that manifests through several symptoms from early adulthood. Numerous studies over the last decades have led to significant advances in increasing our understanding of the factors involved in SCZ. For example, mass spectrometry-based proteomic analysis has provided important insights by uncovering protein dysfunctions inherent to SCZ. Here, we present a comprehensive analysis of the nuclear proteome of postmortem brain tissues from corpus callosum (CC) and anterior temporal lobe (ATL). We show an overview of the role of deregulated nuclear proteins in these two main regions of the brain: the first, mostly composed of glial cells and axons of neurons, and the second, represented mainly by neuronal cell bodies. These samples were collected from SCZ patients in an attempt to characterize the role of the nucleus in the disease process. With the ATL nucleus enrichment, we found 224 proteins present at different levels, and 76 of these were nuclear proteins. In the CC analysis, we identified 119 present at different levels, and 24 of these were nuclear proteins. The differentially expressed nuclear proteins of ATL are mainly associated with the spliceosome, whereas those of the CC region are associated with calcium/calmodulin signaling.

Synaptosomal Proteome of the Orbitofrontal Cortex from Schizophrenia Patients Using Quantitative Label-Free and iTRAQ-Based Shotgun Proteomics.

Schizophrenia is a chronic and incurable neuropsychiatric disorder that affects about one percent of the world population. The proteomic characterization of the synaptosome fraction of the orbitofrontal cortex is useful for providing valuable information about the molecular mechanisms of synaptic functions in these patients. Quantitative analyses of synaptic proteins were made with eight paranoid schizophrenia patients and a pool of eight healthy controls free of mental diseases. Label-free and iTRAQ labeling identified a total of 2018 protein groups. Statistical analyses revealed 12 and 55 significantly dysregulated proteins by iTRAQ and label-free, respectively. Quantitative proteome analyses showed an imbalance in the calcium signaling pathway and proteins such as reticulon-1 and cytochrome c, related to endoplasmic reticulum stress and programmed cell death. Also, it was found that there is a significant increase in limbic-system-associated membrane protein and α-calcium/calmodulin-dependent protein kinase II, associated with the regulation of human behavior. Our data contribute to a better understanding about apoptosis as a possible pathophysiological mechanism of this disease as well as neural systems supporting social behavior in schizophrenia. This study also is a joint effort of the Chr 15 C-HPP team and the Human Brain Proteome Project of B/D-HPP. All MS proteomics data are deposited in the ProteomeXchange Repository under PXD006798.

Aerobic exercise and its effects on cognition in schizophrenia.

PURPOSE OF REVIEW: Schizophrenia is a severe neuropsychiatric disorder with incomplete remission because of negative and cognitive symptoms in a large proportion of patients. Antipsychotic medication is successful in modulating positive symptoms, but only to a lower extent negative symptoms including cognitive dysfunction. Therefore, development of innovative add-on treatment is highly needed. In this review, recent evidence from clinical studies reveals effects of aerobic exercise on cognitive deficits in schizophrenia patients. RECENT FINDINGS: First studies and meta-analyses on aerobic exercise in schizophrenia patients have shown effects on positive, negative, and global symptoms and cognitive domains such as global cognition, working memory, and attention. Underlying neurobiological mechanisms such as neuroplasticity-related synaptogenesis and neurogenesis have been identified in animal studies and possibly mediate effects of aerobic exercise on brain structure and function. SUMMARY: Different aspects of methods (e.g., endurance training versus yoga and Tai Chi), length and dose of the intervention, supervision of patients by sports therapists as well as maintenance of cognitive improvement after cessation of training have been raised by previous studies. However, minimal and most effective dosage of the intervention and mechanisms underlying changes in neuroplasticity need to be answered in future basic and large-scale randomized clinical trials.

Differential proteome and phosphoproteome may impact cell signaling in the corpus callosum of schizophrenia patients.

Schizophrenia is a multifactorial disease in both clinical and molecular terms. Thus, depicting the molecular aspects of the disease will contribute to the understanding of its biochemical mechanisms and consequently may lead to the development of new treatment strategies. The protein phosphorylation/dephosphorylation switch acts as the main mechanism for regulating cellular signaling. Moreover, approximately onethird of human proteins are phosphorylable. Thus, identifying proteins differentially phosphorylated in schizophrenia postmortem brains may improve our understanding of the molecular basis of brain function in this disease. Hence, we quantified the phosphoproteome of corpus callosum samples collected post mortem from schizophrenia patients and healthy controls. We used state-of-the-art, bottom-up shotgun mass spectrometry in a two-dimensional liquid chromatography-tandem mass spectrometry setup in the MSE mode with label-free quantification. We identified 60,634 peptides, belonging to 3283 proteins. Of these, 68 proteins were differentially phosphorylated, and 56 were differentially expressed. These proteins are mostly involved in signaling pathways, such as ephrin B and ciliary neurotrophic factor signaling. The data presented here are novel because this was the very first phosphoproteome analysis of schizophrenia brains. They support the important role of glial cells, especially astrocytes, in schizophrenia and help to further the understanding of the molecular aspects of this disease. Our findings indicate a need for further studies on cell signaling, which might shape the development of treatment strategies.

Proteomics of the corpus callosum unravel pivotal players in the dysfunction of cell signaling, structure, and myelination in schizophrenia brains.

Schizophrenia is an incurable and debilitating mental disorder that may affect up to 1% of the world population. Morphological, electrophysiological, and neurophysiological studies suggest that the corpus callosum (CC), which is the largest portion of white matter in the human brain and responsible for inter-hemispheric communication, is altered in schizophrenia patients. Here, we employed mass spectrometry-based proteomics to investigate the molecular underpinnings of schizophrenia. Brain tissue samples were collected postmortem from nine schizophrenia patients and seven controls at the University of Heidelberg, Germany. Because the CC has a signaling role, we collected cytoplasmic (soluble) proteins and submitted them to nano-liquid chromatography-mass spectrometry (nano LC-MS/MS). Proteomes were quantified by label-free spectral counting. We identified 5678 unique peptides that corresponded to 1636 proteins belonging to 1512 protein families. Of those proteins, 65 differed significantly in expression: 28 were upregulated and 37 downregulated. Our data increased significantly the knowledge derived from an earlier proteomic study of the CC. Among the differentially expressed proteins are those associated with cell growth and maintenance, such as neurofilaments and tubulins; cell communication and signaling, such as 14-3-3 proteins; and oligodendrocyte function, such as myelin basic protein and myelin-oligodendrocyte glycoprotein. Additionally, 30 of the differentially expressed proteins were found previously in other proteomic studies in postmortem brains; this overlap in findings validates the present study and indicates that these proteins may be markers consistently associated with schizophrenia. Our findings increase the understanding of schizophrenia pathophysiology and may serve as a foundation for further treatment strategies.

MK-801 treatment affects glycolysis in oligodendrocytes more than in astrocytes and neuronal cells: insights for schizophrenia.

Schizophrenia is a debilitating mental disorder, affecting more than 30 million people worldwide. As a multifactorial disease, the underlying causes of schizophrenia require analysis by multiplex methods such as proteomics to allow identification of whole protein networks. Previous post-mortem proteomic studies on brain tissues from schizophrenia patients have demonstrated changes in activation of glycolytic and energy metabolism pathways. However, it is not known whether these changes occur in neurons or in glial cells. To address this question, we treated neuronal, astrocyte, and oligodendrocyte cell lines with the NMDA receptor antagonist MK-801 and measured the levels of six glycolytic enzymes by Western blot analysis. MK-801 acts on the glutamatergic system and has been proposed as a pharmacological means of modeling schizophrenia. Treatment with MK-801 resulted in significant changes in the levels of glycolytic enzymes in all cell types. Most of the differences were found in oligodendrocytes, which had altered levels of hexokinase 1 (HK1), enolase 2 (ENO2), phosphoglycerate kinase (PGK), and phosphoglycerate mutase 1 after acute MK-801 treatment (8 h), and HK1, ENO2, PGK, and triosephosphate isomerase (TPI) following long term treatment (72 h). Addition of the antipsychotic clozapine to the cultures resulted in counter-regulatory effects to the MK-801 treatment by normalizing the levels of ENO2 and PGK in both the acute and long term cultures. In astrocytes, MK-801 affected only aldolase C (ALDOC) under both acute conditions and HK1 and ALDOC following long term treatment, and TPI was the only enzyme affected under long term conditions in the neuronal cells. In conclusion, MK-801 affects glycolysis in oligodendrocytes to a larger extent than neuronal cells and this may be modulated by antipsychotic treatment. Although cell culture studies do not necessarily reflect the in vivo pathophysiology and drug effects within the brain, these results suggest that neurons, astrocytes, and oligodendrocytes are affected differently in schizophrenia. Employing in vitro models using neurotransmitter agonists and antagonists may provide new insights about the pathophysiology of schizophrenia which could lead to a novel system for drug discovery.

Disturbed macro-connectivity in schizophrenia linked to oligodendrocyte dysfunction: from structural findings to molecules.

Schizophrenia is a severe psychiatric disorder with multi-factorial characteristics. A number of findings have shown disrupted synaptic connectivity in schizophrenia patients and emerging evidence suggests that this results from dysfunctional oligodendrocytes, the cells responsible for myelinating axons in white matter to promote neuronal conduction. The exact cause of this is not known, although recent imaging and molecular profiling studies of schizophrenia patients have identified changes in white matter tracts connecting multiple brain regions with effects on protein signaling networks involved in the myelination process. Further understanding of oligodendrocyte dysfunction in schizophrenia could lead to identification of novel drug targets for this devastating disease.

The impact of environmental factors in severe psychiatric disorders.

During the last decades, schizophrenia has been regarded as a developmental disorder. The neurodevelopmental hypothesis proposes schizophrenia to be related to genetic and environmental factors leading to abnormal brain development during the pre- or postnatal period. First disease symptoms appear in early adulthood during the synaptic pruning and myelination process. Meta-analyses of structural MRI studies revealing hippocampal volume deficits in first-episode patients and in the longitudinal disease course confirm this hypothesis. Apart from the influence of risk genes in severe psychiatric disorders, environmental factors may also impact brain development during the perinatal period. Several environmental factors such as antenatal maternal virus infections, obstetric complications entailing hypoxia as common factor or stress during neurodevelopment have been identified to play a role in schizophrenia and bipolar disorder, possibly contributing to smaller hippocampal volumes. In major depression, psychosocial stress during the perinatal period or in adulthood is an important trigger. In animal studies, chronic stress or repeated administration of glucocorticoids have been shown to induce degeneration of glucocorticoid-sensitive hippocampal neurons and may contribute to the pathophysiology of affective disorders. Epigenetic mechanisms altering the chromatin structure such as histone acetylation and DNA methylation may mediate effects of environmental factors to transcriptional regulation of specific genes and be a prominent factor in gene-environmental interaction. In animal models, gene-environmental interaction should be investigated more intensely to unravel pathophysiological mechanisms. These findings may lead to new therapeutic strategies influencing epigenetic targets in severe psychiatric disorders.

Ten years of proteomics in multiple sclerosis.

Multiple sclerosis, which is the most common cause of chronic neurological disability in young adults, is an inflammatory, demyelinating, and neurodegenerative disease of the CNS, which leads to the formation of multiple foci of demyelinated lesions in the white matter. The diagnosis is based currently on magnetic resonance image and evidence of dissemination in time and space. However, this could be facilitated if biomarkers were available to rule out other disorders with similar symptoms as well as to avoid cerebrospinal fluid analysis, which requires an invasive collection. Additionally, the molecular mechanisms of the disease are not completely elucidated, especially those related to the neurodegenerative aspects of the disease. The identification of biomarker candidates and molecular mechanisms of multiple sclerosis may be approached by proteomics. In the last 10 years, proteomic techniques have been applied in different biological samples (CNS tissue, cerebrospinal fluid, and blood) from multiple sclerosis patients and in its experimental model. In this review, we summarize these data, presenting their value to the current knowledge of the disease mechanisms, as well as their importance in identifying biomarkers or treatment targets.

Increased cell proliferation in the rat anterior cingulate cortex following neonatal hypoxia: relevance to schizophrenia.

As a consequence of obstetric complications, neonatal hypoxia has been discussed as an environmental factor in the pathophysiology of schizophrenia. However, the biological consequences of hypoxia are unclear. The neurodevelopmental hypothesis of schizophrenia suggests that the onset of abnormal brain development and neuropathology occurs perinatally, whereas symptoms of the disease appear in early adulthood. In our animal model of chronic neonatal hypoxia, we have detected behavioral alterations resembling those known from schizophrenia. Disturbances in cell proliferation possibly contribute to the pathophysiology of this disease. In the present study, we used postnatal rats to investigate cell proliferation in several brain areas following neonatal hypoxia. Rats were repeatedly exposed to hypoxia (89 % N(2), 11 % O(2)) from postnatal day (PD) 4-8. We then evaluated cell proliferation on PD 13 and 39, respectively. These investigations were performed in the anterior cingulate cortex (ACC), caudate-putamen (CPU), dentate gyrus, and subventricular zone. Rats exposed to hypoxia exhibited increased cell proliferation in the ACC at PD 13, normalizing at PD 39. In other brain regions, no alterations have been detected. Additionally, hypoxia-treated rats showed decreased CPU volume at PD 13. The results of the present study on the one hand support the assumption of chronic hypoxia influencing transient cell proliferation in the ACC, and on the other hand reveal normalization during ageing.

Estudos transcriptômicos no contexto da conectividade perturbada em esquizofrenia / Transcriptome studies in the context of disturbed connectivity in schizophrenia

Esquizofrenia é uma severa doença neurobiológica com fatores genéticos e ambientais desempenhando um papel na fisiopatologia. Diversas regiões cerebrais têm sido implicadas no processo da doença e estão conectadas em complexos circuitos neuronais. Nos níveis molecular e celular, a conectividade afetada entre essas regiões, envolvendo mielinização disfuncional dos axônios neuronais, bem como as alterações no nível sináptico e metabolismo energético levando a distúrbios na plasticidade sináptica, são os maiores achados em estudos post-mortem. Estudos de microarranjos investigando a expressão gênica contribuíram para os achados de alterações em vias complexas em regiões cerebrais relevantes na esquizofrenia. Além disso, estudos utilizando microdissecção e captura a laser permitiram a investigação da expressão gênica em grupos específicos de neurônios. Entretanto, deve ser mantido em mente que em estudos post-mortem, confusos efeitos de medicação, qualidade de RNAm, bem como capacidade de mecanismos regenerativos neuroplásticos do cérebro em indivíduos com história de vida de esquizofrenia, podem influenciar o complexo padrão de alterações no nível molecular. Apesar dessas limitações, estudos transcriptômicos livres de hipóteses em tecido cerebral de pacientes esquizofrênicos oferecem uma possibilidade única para aprender mais sobre os mecanismos subjacentes, levando a novas ópticas da fisiopatologia da doença

Schizophrenia is a severe neurobiological disease with genetic and environmental factors playing a role in the pathophysiology. Several brain regions have been implicated in the disease process and are connected in complex neuronal circuits. On the cellular and molecular level, affected connectivity between these regions, involving dysfunctional myelination of neuronal axons, as well as alterations on the synaptic level and energy metabolism of neurons leading to disturbances in synaptic plasticity are major findings in post-mortem studies. Microarray studies investigating genome-wide gene expression have contributed to the findings of alterations in complex pathways in relevant brain regions in schizophrenia. Moreover, first Laser-capture Microdissection studies allowed the investigation of gene expression in specific groups of neurons. However, it must be kept in mind that in post-mortem studies confounding effects of medication, mRNA quality as well as the capability of the brain for neuroplastic regenerative mechanisms in individuals with a lifetime history of schizophrenia may influence the complex pattern of alterations on the molecular level. Despite these limitations, hypothesis-free transcriptome studies in brain tissue from schizophrenia patients offer a unique possibility to learn more about underlying mechanisms, leading to new insights in the pathophysiology of the disease

The role of the cerebellum in schizophrenia: from cognition to molecular pathways.

Beside its role in motor coordination, the cerebellum is involved in cognitive function such as attention, working memory, verbal learning, and sensory discrimination. In schizophrenia, a disturbed prefronto-thalamo-cerebellar circuit has been proposed to play a role in the pathophysiology. In addition, a deficit in the glutamatergic N-methyl-D-aspartate (NMDAf) receptor has been hypothesized. The risk gene neuregulin 1 may play a major role in this process. We demonstrated a higher expression of the NMDA receptor subunit 2D in the right cerebellar regions of schizophrenia patients, which may be a secondary upregulation due to a dysfunctional receptor. In contrast, the neuregulin 1 risk variant containing at least one C-allele was associated with decreased expression of NMDA receptor subunit 2C, leading to a dysfunction of the NMDA receptor, which in turn may lead to a dysfunction of the gamma amino butyric acid (GABA) system. Accordingly, from post-mortem studies, there is accumulating evidence that GABAergic signaling is decreased in the cerebellum of schizophrenia patients. As patients in these studies are treated with antipsychotics long term, we evaluated the effect of long-term haloperidol and clozapine treatment in an animal model. We showed that clozapine may be superior to haloperidol in restoring a deficit in NMDA receptor subunit 2C expression in the cerebellum. We discuss the molecular findings in the light of the role of the cerebellum in attention and cognitive deficits in schizophrenia.

Perinatal asphyxia: current status and approaches towards neuroprotective strategies, with focus on sentinel proteins.

Delivery is a stressful and risky event menacing the newborn. The mother-dependent respiration has to be replaced by autonomous pulmonary breathing immediately after delivery. If delayed, it may lead to deficient oxygen supply compromising survival and development of the central nervous system. Lack of oxygen availability gives rise to depletion of NAD(+) tissue stores, decrease of ATP formation, weakening of the electron transport pump and anaerobic metabolism and acidosis, leading necessarily to death if oxygenation is not promptly re-established. Re-oxygenation triggers a cascade of compensatory biochemical events to restore function, which may be accompanied by improper homeostasis and oxidative stress. Consequences may be incomplete recovery, or excess reactions that worsen the biological outcome by disturbed metabolism and/or imbalance produced by over-expression of alternative metabolic pathways. Perinatal asphyxia has been associated with severe neurological and psychiatric sequelae with delayed clinical onset. No specific treatments have yet been established. In the clinical setting, after resuscitation of an infant with birth asphyxia, the emphasis is on supportive therapy. Several interventions have been proposed to attenuate secondary neuronal injuries elicited by asphyxia, including hypothermia. Although promising, the clinical efficacy of hypothermia has not been fully demonstrated. It is evident that new approaches are warranted. The purpose of this review is to discuss the concept of sentinel proteins as targets for neuroprotection. Several sentinel proteins have been described to protect the integrity of the genome (e.g. PARP-1; XRCC1; DNA ligase IIIα; DNA polymerase ß, ERCC2, DNA-dependent protein kinases). They act by eliciting metabolic cascades leading to (i) activation of cell survival and neurotrophic pathways; (ii) early and delayed programmed cell death, and (iii) promotion of cell proliferation, differentiation, neuritogenesis and synaptogenesis. It is proposed that sentinel proteins can be used as markers for characterising long-term effects of perinatal asphyxia, and as targets for novel therapeutic development and innovative strategies for neonatal care.

The role of the cerebellum in schizophrenia: from cognition to molecular pathways

Beside its role in motor coordination, the cerebellum is involved in cognitive function such as attention, working memory, verbal learning, and sensory discrimination. In schizophrenia, a disturbed prefronto-thalamo-cerebellar circuit has been proposed to play a role in the pathophysiology. In addition, a deficit in the glutamatergic N-methyl-D-aspartate (NMDAf) receptor has been hypothesized. The risk gene neuregulin 1 may play a major role in this process. We demonstrated a higher expression of the NMDA receptor subunit 2D in the right cerebellar regions of schizophrenia patients, which may be a secondary upregulation due to a dysfunctional receptor. In contrast, the neuregulin 1 risk variant containing at least one C-allele was associated with decreased expression of NMDA receptor subunit 2C, leading to a dysfunction of the NMDA receptor, which in turn may lead to a dysfunction of the gamma amino butyric acid (GABA) system. Accordingly, from post-mortem studies, there is accumulating evidence that GABAergic signaling is decreased in the cerebellum of schizophrenia patients. As patients in these studies are treated with antipsychotics long term, we evaluated the effect of long-term haloperidol and clozapine treatment in an animal model. We showed that clozapine may be superior to haloperidol in restoring a deficit in NMDA receptor subunit 2C expression in the cerebellum. We discuss the molecular findings in the light of the role of the cerebellum in attention and cognitive deficits in schizophrenia.

The impact of antipsychotic drugs on food intake and body weight and on leptin levels in blood and hypothalamic ob-r leptin receptor expression in wistar rats.

OBJECTIVES: The aim of our study was to investigate the impact of typical and atypical antipsychotic drugs on leptin concentration in blood and changes in the receptor expression in the hypothalamus of male Wistar rats. METHODS: From the age of 13 to 18 weeks, three groups of 20 animals were fed an average dose of 3.5 + 0.03 mg/ kg body weight (BW) haloperidol; 30.6 + 0.22 mg/kg BW clozapine; or 14.9 + 0.13 mg/kg BW ziprasidone in ground food pellets containing 15% fat. Twenty control animals received no drugs. Blood samples were taken at week 14, 16, and 19. Locomotor activity and exploratory behavior were measured using the alcove test at weeks 15 and 17. The expression of the hypothalamic leptin receptor in rat brains was determined by using a Western blot. RESULTS: Rats medicated with haloperidol and ziprasidone showed a significantly decreased percentage weight gain and food consumption. We observed no differences in the alcove test, but locomotor activity was significantly reduced in the haloperidol group. Except for rats in the clozapine and ziprasidone groups, after 2 weeks of drug application, we found no changes in the leptin blood concentrations among the four groups or animals within each group. Moreover, we did not find specific differences in hypothalamic leptin receptor expression among the groups. CONCLUSION: We concluded that in male Wistar rats during this treatment period, the tested drugs did not act directly on the leptin regulatory system. We recommend further studies using long-term treatment of different rat strains.

Thalamic nuclear abnormalities as a contributory factor in sudden cardiac deaths among patients with schizophrenia.

Patients with schizophrenia have a two- to three-fold increased risk of premature death as compared to patients without this disease. It has been established that patients with schizophrenia are at a high risk of developing cardiovascular disease. Moreover, an important issue that has not yet been explored is a possible existence of a "cerebral" focus that could trigger sudden cardiac death in patients with schizophrenia. Along these lines, several structural and functional alterations in the thalamic complex are evident in patients with schizophrenia and have been correlated with the symptoms manifested by these patients. With regard to abnormalities on the cellular and molecular level, previous studies have shown that schizophrenic patients have fewer neuronal projections from the thalamus to the prefrontal cortex as well as a reduced number of neurons, a reduced volume of either the entire thalamus or its subnuclei, and abnormal glutamate signaling. According to the glutamate hypothesis of schizophrenia, hypofunctional corticostriatal and striatothalamic projections are directly involved in the pathophysiology of the disease. Animal and post-mortem studies have provided a large amount of evidence that links the sudden unexpected death in epilepsy (SUDEP) that occurs in patients with schizophrenia and epilepsy to thalamic changes. Based on the results of these prior studies, it is clear that further research regarding the relationship between the thalamus and sudden cardiac death is of vital importance.