neuropeptide-y and Schizophrenia

The abundantly expressed neuropeptide Y (NPY) has potent effects on feeding, body weight, and blood pressure, and exhibits important functions in various behavioral domains such as motor activity and anxiety. The potent neurotransmitter exerts its biological effects through at least five G-protein coupled receptors termed Y(1), Y(2), Y(4), Y(5), and y(6). The behavioral profile of NPY function has been extensively studied using traditional pharmacological and classic genetic animal models. Based on these studies, variations in the profile of NPY and its receptors have been found. To limit the variability and inconsistencies in the behavioral profile of NPY and to clarify its effects on certain domains in further detail, it is important to design a rational standardized strategy for behavioral testing, using a complement of different well-established and reproducible tests. This strategy can minimize the risk that false positive or false negative results lead to a contradictory and inconsistent behavioral characterization of NPY function. Ideally, such screening should be composed of an initial monitoring of general health, sensory functions, and motor abilities, before specific behavioral domains such as anxiety or aggression are investigated using a multi-tiered phenotyping approach. In this review, we will focus on a brief description of the latest insights into the behavioral profile of NPY in the selective lesser investigated domains such as aggression and depression-schizophrenia-related behaviors. We will combine this information with possible strategies to evaluate the different specific phenotypes in more detail.

Topics: Aggression; Depression; Humans; Neuropeptide Y; Schizophrenia

It is known that 9-13% of individuals with a diagnosis of schizophrenia commits suicide. In addition, patients with schizophrenia have approximately a 50% lifetime risk for attempting suicide. The authors review the identified risk factors for suicide in schizophrenia. The most significant risk factors include the age of the patient, male gender, depression, presence of positive symptoms and substance abuse. There is evidence that implicates the serotonin system in the suicide of individuals with schizophrenia. Overactivity of the hypothalamo-pituitary-adrenal axis has also been reported in individuals who went on to attempt suicide. The authors review the molecular biology of suicide in schizophrenia. With regard to prevention of suicide, pharmacological intervention with typical antipsychotics and antidepressants may be helpful. It is suggested that atypical anti-psychotics, in particular clozapine may provide additional benefit in reducing the rate of suicide attempts. The authors emphasise the importance of early treatment of individuals with a diagnosis of schizophrenia, the role of maintenance therapy and the importance of a collaborative approach between in- and outpatient services.

Topics: Age Factors; Antidepressive Agents; Antipsychotic Agents; Clozapine; Depression; Female; Humans; Male; Neuropeptide Y; Polymorphism, Genetic; Risk Factors; Schizophrenia; Schizophrenic Psychology; Serotonin Plasma Membrane Transport Proteins; Sex Factors; Substance-Related Disorders; Suicide; Suicide Prevention

Although several studies have summarized the effects of neuropeptide Y (NPY) in the central nervous system, its role in psychopharmacotherapy has not been reviewed in detail. For the last few years, there has been an increase in the number of studies on the suggested role of NPY in the benefits of treatment for mental disorders. Our review focuses on the possible involvement of altered NPY system activity in the effects of antianxiety, antidepressant and antipsychotic therapies. Potential sites and receptors, which are implicated in mediating the NPY effects of psychotropic drugs, have been described. We discuss the significance of alterations in the brain NPY system for the development of new methods of treatment for mental disorders.

Topics: Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Depressive Disorder; Humans; Neuropeptide Y; Psychotropic Drugs; Schizophrenia; Schizophrenic Psychology

Since its discovery in 1982, neuropeptide Y (NPY) has been shown to have numerous effects mediated by a growing number of NPY receptors in both the CNS and peripheral nervous system. Perhaps best appreciated is the role of NPY in the control of systemic blood pressure, together with its effects on feeding, anxiety and memory. However, recent evidence increasingly supports an important role for NPY in mediating analgesia and hyperalgesia by distinct central and peripheral mechanisms. In this review we concentrate on this important aspect of NPY pharmacology and consider mechanisms controlling the expression of NPY and its receptors. In addition, we also present the more recent data describing the other possible roles for NPY-NPY agonists and antagonists may be useful in the treatment of conditions as varied as anorexia, epilepsy, anxiety, depression, hypertension and heart failure.

Topics: Analgesics; Animals; Anti-Anxiety Agents; Antihypertensive Agents; Appetite Stimulants; Cardiovascular Diseases; Central Nervous System; Depression; Humans; Hyperalgesia; Memory Disorders; Neuropeptide Y; Peripheral Nervous System; Receptors, Neuropeptide Y; Schizophrenia

During the last years, due to the availability of selective ligands, numerous investigations have been dedicated to sigma receptors. The existence of different subtypes of these receptors is now accepted; their endogenous ligand has not yet been identified, but some candidates have been proposed. Evidence suggests that one of their major roles might be to regulate the activity of the glutamatergic system via the N-methyl-D-aspartate receptor. The potential involvement of sigma receptors in psychiatry was suggested by the psychotomimetic effects of their earliest ligands and the fact that several neuroleptics have a high affinity for them. Recently, new arguments have strengthened this hypothesis: some molecules with high sigma affinity but low dopaminergic affinity display a "neuroleptic-like" pharmacological profile; post-mortem studies have shown a reduction of sigma binding sites in the brain of patients with schizophrenia; cocaine, which can induce psychotic episodes, has high affinity for sigma receptors. Hence, by modulating the glutamatergic inputs, by regulating directly the firing activity of dopaminergic neurons, or by both mechanisms, sigma receptors could be involved in the pathophysiology and/or in the treatment of schizophrenia.

Topics: Binding Sites; Cocaine; Female; Glutamates; Hippocampus; Humans; Ligands; Male; Neuropeptide Y; Psychiatry; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Schizophrenia

Modulation of glutamatergic neurotransmission in schizophrenia by sarcosine leads to a reduction in primary negative symptoms, while its metabolic profile is safe. In order to extend research in the area, we assessed serum levels of neuropeptide Y (NPY), a hypothalamic hormone related to anxiety and depression, also involved in mechanisms inducing weight gain. Additionally, we analyzed associations between NPY concentrations and its changes with severity of symptoms and metabolic parameters.. A prospective 6-month, randomized, double-blind placebo-controlled trial was completed by 57 subjects with chronic schizophrenia with predominant negative symptoms and stable antipsychotic treatment. The participants received 2 g of sarcosine (n = 28) or placebo (n = 29) daily. We assessed serum NPY concentrations and severity of symptoms (with the Positive and Negative Syndrome Scale [PANSS] and Calgary Depression Scale for Schizophrenia) at the beginning of the study, after 6 weeks and 6 months.. Sarcosine did not affect NPY levels in all time points. The highest decrease in NPY concentrations was observed in the subjects who were initially depressed, who became euthymic at the last visit. We noticed an improvement in the total PANSS score, and negative symptom and general psychopathology subscales in the sarcosine group, however, without any correlation with NPY levels.. The use of sarcosine does not change NPY levels. Peripheral NPY concentrations may be related to depressive symptoms in schizophrenia.

Topics: Antipsychotic Agents; DEAE-Dextran; Double-Blind Method; Drug Therapy, Combination; Humans; Neuropeptide Y; Prospective Studies; Psychiatric Status Rating Scales; Sarcosine; Schizophrenia; Treatment Outcome

Cumulative evidence indicates that neuropeptides play a role in the pathophysiology of schizophrenia. Early data showed increased neuropeptide Y (NPY) in cerebrospinal fluid (CSF) from schizophrenia patients and data from rodents show that antipsychotic drugs modulate NPY levels in and release from selected rat brain regions. In view of these findings we investigated whether the atypical antipsychotic quetiapine, originally used as an antipsychotic but subsequently shown to be efficient also in major depressive disorder and in both poles of bipolar disorder, would affect NPY-like immunoreactivity (-LI), and corticotropin-releasing hormone (CRH)-LI levels in CSF of schizophrenia patients. NPY-LI and CRH-LI in CSF were determined in 22 patients with schizophrenia. Lumbar puncture was performed at baseline and again after 4 wk of quetiapine treatment (600 mg/d). Patients were assessed with the Positive and Negative Syndrome Scale (PANSS) at baseline and at weekly intervals. Quetiapine treatment was associated with a significant increase in NPY-LI (p<0.001) and decrease in CRH-LI (p<0.01). Stepwise multiple regression analysis revealed that ΔNPY-LI and ΔCRH-LI levels predicted 63% (p<0.001) of the variability of the ΔPANSS total score, ΔNPY-LI 42% (p<0.05) of the ΔPANSS anxiety items (G2) and ΔCRH-LI 40% (p=0.05) of the ΔPANSS depression items (G6). These results suggest that while quetiapine's effects on monoamines are probably related to its antipsychotic properties, the modulation of NPY and CRH accounts for its antidepressant and anxiolytic effects and can be markers of response.

Topics: Adolescent; Adult; Analysis of Variance; Antipsychotic Agents; Corticotropin-Releasing Hormone; Dibenzothiazepines; Electrocardiography; Electroencephalography; Female; Humans; Male; Middle Aged; Neuropeptide Y; Quetiapine Fumarate; Regression Analysis; ROC Curve; Schizophrenia; Tandem Mass Spectrometry; Treatment Outcome; Young Adult

Body mass index (BMI) increase is an undesired effect associated with antipsychotics, and crucial for patients' global health and treatment compliance. We aimed to investigate the relation between BMI during olanzapine or haloperidol treatments and leptin, neuropeptide Y (NPY), adiponectin and lipid serum levels.. In this 9-month, randomized and naturalist study, 34 male patients, 18 on olanzapine and 16 on haloperidol group were enrolled, all were under monotherapy. Patient outcome was evaluated with positive and negative syndrome scale (PANSS) at every 3-month period. In each visit, BMI, leptin, NPY, lipid, olanzapine or haloperidol levels were also monitored.. Leptin levels positively correlated with BMI in olanzapine (r=0.64, p<0.001) and haloperidol (r=0.73, p<0.001) groups; only in olanzapine patients, the former also correlated with PANSS score (r=0.54, p<0.05). NPY levels negatively correlated with olanzapine levels (r=− 0.65, p<0.01). Adiponectin levels had not significantly varied.. Antipsychotics probably interfere on leptin and NPY signalling ways and disturb these hormones in eating behaviour control.

Topics: Adiponectin; Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Biomarkers; Body Mass Index; Haloperidol; Humans; Leptin; Lipids; Male; Middle Aged; Neuropeptide Y; Olanzapine; Psychiatric Status Rating Scales; Schizophrenia

Weight gain is an important side effect of antipsychotic (AP) treatment. Weight is regulated by multiple systems, including leptin, neuropeptide Y (NPY) and gonadal steroids. The aim was to investigate whether AP-induced weight gain was related to leptin and NPY abnormalities and whether these were associated with a disruption of gonadal steroid production.. Twenty two female patients with schizophrenia receiving standard AP treatment were studied over a 3-month period. Plasma leptin, NPY, gonadal steroids and their regulators were measured along with weight and BMI.. Weight, leptin and testosterone levels increased over time. There were significant relationships between a change in oestrogen levels and both a change in NPY levels and a change in BMI. Change in BMI, weight and leptin all correlated strongly with a change in the testosterone/luteinizing hormone ratio.. AP treatment results in increase in weight over time and this increase is accompanied by increased leptin levels. AP-induced weight gain is also associated with disruption of the hypothalamic-pituitary-gonadal axis. Altered regulation of NPY, either through abnormal leptin control or serotonin blockade, is a possible explanation for the effects of AP medication on both weight and gonadal steroid levels.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Female; Gonadal Steroid Hormones; Humans; Leptin; Middle Aged; Neuropeptide Y; Olanzapine; Pirenzepine; Radioimmunoassay; Risperidone; Schizophrenia; Time Factors; Weight Gain

The aim of this study is to analyze whether clozapine serum concentration may affect fasting serum levels of several appetite regulating peptides: CART, PYY(1-36), NPY, AgRP, des-acylated ghrelin, leptin and obestatin. Serum concentration of clozapine and fasting serum levels of des-acylated ghrelin, neuropeptide Y (NPY), agouti-related protein (AgRP), peptide YY (PYY(1-36)), cocaine- and amphetamine-regulated transcript (CART), leptin and obestatin were measured in 30 subjects with schizophrenia on clozapine monotherapy. Leptin concentration was negatively correlated with clozapine dose (r = -0.53, p = 0.002), while NPY concentration was negatively correlated with clozapine concentration (r = -0.55, p = 0.01). Correlations with other peptides were not significant. We cannot conclude that serum concentration of clozapine is directly associated with increased or decreased level of appetite-regulating peptides.

Topics: Adult; Agouti-Related Protein; Animals; Antipsychotic Agents; Appetite; Clozapine; Dose-Response Relationship, Drug; Fasting; Female; Ghrelin; Humans; Leptin; Male; Middle Aged; Neuropeptide Y; Peptide Hormones; Schizophrenia; Young Adult

Growing evidence points to a key role for somatostatin (SST) in schizophrenia (SZ) and bipolar disorder (BD). In the amygdala, neurons expressing SST play an important role in the regulation of anxiety, which is often comorbid in these disorders. We tested the hypothesis that SST-immunoreactive (IR) neurons are decreased in the amygdala of subjects with SZ and BD. Evidence for circadian SST expression in the amygdala and disrupted circadian rhythms and rhythmic peaks of anxiety in BD suggest a disruption of rhythmic expression of SST in this disorder.. Amygdala sections from 12 SZ, 15 BD, and 15 control subjects were processed for immunocytochemistry for SST and neuropeptide Y, a neuropeptide partially coexpressed in SST-IR neurons. Total numbers (N. SST-IR neurons were decreased in the lateral amygdala nucleus in BD (N. Decreased SST-IR neurons in the amygdala of patients with SZ and BD, interpreted here as decreased SST expression, may disrupt responses to fear and anxiety regulation in these individuals. In BD, our findings raise the possibility that morning peaks of anxiety depend on a disruption of circadian regulation of SST expression in the amygdala.

Topics: Amygdala; Bipolar Disorder; Circadian Rhythm; Female; Humans; Male; Neurons; Neuropeptide Y; Schizophrenia; Somatostatin

Antipsychotic-induced weight gain (AIWG) leads to metabolic consequences and comorbidity, social stigmatization and nonadherence in patients with schizophrenia. Neuropeptide Y (NPY) has an important role in appetite and body weight regulation. Associations between AIWG and serum NPY levels, and genetic polymorphisms (SNPs) associated with its serum levels have been little studied in these patients.. Associations between serum NPY concentration and other metabolic and inflammatory markers, and 215 SNPs in 21 genes (NPY gene, NPY receptor genes and genes encoding arcuate nucleus NPY neuron receptors) were studied in 180 patients with schizophrenia on clozapine treatment.. Serum NPY level does not seem to be a feasible biomarker of AIWG. Serum NPY level alterations are not significantly associated with the candidate gene polymorphisms studied.

Topics: Adult; Animals; Antipsychotic Agents; Arcuate Nucleus of Hypothalamus; Clozapine; Female; Gene Frequency; Humans; Male; Neuropeptide Y; Phenotype; Receptors, Neuropeptide Y; Schizophrenia

Neuropeptide Y (NPY) has been found to play a critical role in various mental functions as a neurotransmitter and is involved in the development of schizophrenia, a particularly intractable psychiatric disease whose precise etiology remains unknown. Recent molecular biological investigations have identified several candidate genes which may be associated with this disease, including disrupted-in-schizophrenia 1 (DISC1). The role of DISC1 would involve neurogenesis and neuronal migration. However, the functional consequences of this gene defect have not yet been fully clarified in neuronal systems. In the present study, to clarify the neuropathological changes associated with the function of DISC1, we explored how DISC1 dysfunction can induce abnormalities in the NPY neuronal network in the central nervous system. We performed immunohistochemical analyses (including the observation of the distribution and density) of prefrontal cortex specimens from DISC1-knockout (KO) mice, which are considered to be a novel animal model of schizophrenia. We then evaluated the number and size of NPY-immunoreactive (NPY-IR) neurons and the length of NPY-IR fibers. The number of NPY-IR neurons and the length of the fibers were decreased in the prefrontal cortex of DISC1-KO mice. The decrease was particularly prominent in the superficial regions, and the distribution of NPY-IR neurons differed between wild-type and DISC1-KO mice. However, the size of the neurons in the cortices of the DISC1-KO and wild-type mice did not differ markedly. Our findings suggest that dysfunction of DISC1 may lead to the alteration of NPY neurons and neurotransmission issues in NPY-containing neuron systems, which seem to play important roles in both the mental function and neuronal development. DISC1 dysfunction may be involved in the pathogenesis of schizophrenia through the impairment of the NPY neuronal network.

Topics: Animals; Disease Models, Animal; Female; Frontal Lobe; Male; Mice, Knockout; Nerve Net; Nerve Tissue Proteins; Neurogenesis; Neurons; Neuropeptide Y; Prefrontal Cortex; Schizophrenia

Neuregulin 1 and its receptor ErbB4 are confirmed risk genes for schizophrenia, but the neuropathological alterations in NRG1-ErbB4 in schizophrenia are unclear. The present investigations therefore focused on determining lamina specific (ErbB4-pan) and quantitative (pan, JMa, JMb, CYT1 and CYT2) ErbB4 mRNA changes in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia. We also determined which neuronal profiles are ErbB4 mRNA+ in the human DLPFC and the relationship between ErbB4 and interneuron marker mRNAs. In situ hybridisation and quantitative PCR measurements were performed to determine changes in ErbB4 splice variant mRNA levels in the DLPFC in schizophrenia (n = 37) compared to control (n = 37) subjects. Cortical neurons expressing ErbB4-pan were labelled with silver grain clusters. Correlations were performed between ErbB4 and interneuron mRNA levels. ErbB4-pan mRNA was significantly increased (layers I, II and V) in the DLPFC in schizophrenia. Silver grain clusters for ErbB4-pan were detected predominantly over small-medium neurons with low-no expression in the larger, paler, more triangular neuronal profiles. ErbB4-JMa mRNA expression was increased in schizophrenia. Somatostatin, neuropeptide Y and vasoactive intestinal peptide mRNAs negatively correlated with ErbB4-JMa mRNA in people with schizophrenia. Our findings demonstrate that ErbB4-pan laminar mRNA expression is elevated (layers I, II, V) in schizophrenia. At the cellular level, ErbB4-pan mRNA+ signal was detected predominantly in interneuron-like neurons. We provide evidence from this independent Australian postmortem cohort that ErbB4-JMa expression is elevated in schizophrenia and is linked to deficits in dendrite-targeting somatostatin, neuropeptide Y and vasoactive intestinal peptide interneurons.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Cohort Studies; Female; Humans; Interneurons; Male; Middle Aged; Neuropeptide Y; Prefrontal Cortex; Receptor, ErbB-4; RNA, Messenger; Schizophrenia; Somatostatin; Vasoactive Intestinal Peptide; Young Adult

There is a lack of biomarkers in schizophrenia and the mechanisms underlying the observed deficits in social functioning are poorly understood. This cohort study aimed to explore whether neurotransmitter neuropeptide Y (NPY) in cerebrospinal fluid (CSF) from patients with schizophrenia is correlated to social function and clinical variables. A further aim was to determine whether baseline levels of NPY were associated with subsequent 3-year outcome. Fifty-six consecutively admitted patients with schizophrenia were included and underwent lumbar puncture and symptom ratings before antipsychotic treatment. NPY levels in CSF were determined by radioimmunoassay. Social function (Social Competence and Social Interest) was assessed by Nurses' Observation Scale for Inpatient Evaluation while psychiatric symptoms were rated using the Comprehensive Psychopathological Rating Scale. Three-year outcome was assessed with the Strauss-Carpenter Outcome Scale. Cross-sectional analysis showed a correlation between level of NPY and Social Competence at index admission (r(s)=0.37, p<0.05). The longitudinal analysis (i.e., at the 3-year follow-up) indicated that, for each standard deviation increase in baseline NPY, there was an increased risk of being unemployed (odds ratio [OR] 2.02, 95% confidence interval [CI] 1.07-3.82), having moderate or severe symptoms (OR 3.09, CI 1.30-7.32) or being hospitalized at least 6 months the previous year (OR 3.24, CI 1.09-9.64). However, NPY was not correlated to Social Interest or clinical variables at index admission. In conclusion, NPY levels in CSF are correlated to Social Competence and seem to predict some aspects of longitudinal outcome in schizophrenia.

Topics: Adult; Alcoholism; Antipsychotic Agents; Cross-Sectional Studies; Employment; Female; Follow-Up Studies; Hospitalization; Humans; Longitudinal Studies; Male; Neuropeptide Y; Odds Ratio; Psychiatric Status Rating Scales; Radioimmunoassay; Schizophrenia; Schizophrenic Psychology; Social Skills; Spinal Puncture; Treatment Outcome

Topics: Exons; Humans; Neuropeptide Y; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Schizophrenia; Suicidal Ideation

Significant body weight gain (BWG) is a serious adverse effect of a number of antipsychotic drugs. Previous studies have demonstrated an influence of clozapine, but not haloperidol, on neuropeptide Y (NPY) expression in the hypothalamus. Because NPY is a potent orexigenic peptide stimulating food intake, and genetic variation of the gene has been shown to influence development of obesity, we investigated the impact of NPY polymorphisms on antipsychotic-induced BWG.We analyzed 5 polymorphisms in the NPY gene (rs10551063, rs16147, rs5573, rs5574, and rs16475) in schizophrenia subjects (n = 226), treated mostly with clozapine and olanzapine for up to 14 weeks. Association was tested using analysis of covariance with change (%) from baseline weight as the dependent variable and duration of treatment and baseline body weight as covariates.In patients of European ancestry who received either clozapine or olanzapine, significant genotypic and allelic association of rs16147 with weight change was observed (P(corrected) = 0.012 and 0.018, respectively). Carriers of the C allele gained significantly more weight compared with individuals with TT genotype (CC + CT vs TT; 5.82% ± 5.6% vs 2.25% ± 4.8%; P= 0.001). Similarly, 2 other polymorphisms (rs5573 and rs5574) were also significantly associated with weight change (P(corrected) = 0.018 and 0.03). In addition, we observed a significant gene-gene interaction between the rs16147 in NPY and rs806378 in cannabinoid receptor 1 (P(corrected) = 0.011).Our observation of association of NPY polymorphisms gives further evidence for a genetic influence on antipsychotic-induced BWG and suggests a role of NPY gene in influencing this complex adverse effect.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Black or African American; Chi-Square Distribution; Clozapine; Female; Gene Frequency; Genotype; Germany; Humans; Male; Middle Aged; Neuropeptide Y; New York; Ohio; Olanzapine; Phenotype; Polymorphism, Single Nucleotide; Receptor, Cannabinoid, CB1; Risk Assessment; Risk Factors; Schizophrenia; Weight Gain; White People; Young Adult

Interstitial white matter neurons (IWMNs) may reflect immature neurons that migrate tangentially to the neocortex from the ganglionic eminence to form cortical interneurons. Alterations of interneuron markers have been detected in gray matter of dorsolateral prefrontal cortex in schizophrenia, and IWMNs are also reported to be altered in schizophrenia. In this study, we considered whether a potential link exists between these two pathological findings.. From a cohort of 29 schizophrenia subjects and 37 control subjects, IWMN densities were determined in the dorsolateral prefrontal cortex by counting neuronal nuclear antigen (NeuN) and somatostatin (SST)-positive cells. Double-label immunofluorescence was carried out to determine the overlap between SST+/NeuN+ and SST+/neuropeptide Y + neurons.. We found that density of NeuN + IWMNs in superficial white matter is significantly increased in schizophrenia subjects compared with control subjects. There was a significant negative correlation between SST mRNA expression in gray matter and NeuN + IWMN density. In schizophrenic patients with increased NeuN IWMN density, the density of SST-expressing neurons in white matter was also higher compared with control subjects. A subpopulation of SST immunopositive cells also show coexpression of neuropeptide Y.. Our study confirmed previous results indicating that the density of NeuN + IWMNs is increased in superficial white matter in schizophrenia. We provide the first evidence that increased IWMN density correlates with a gray matter interneuron deficit, suggesting that migration of interneurons from white matter to the cortex may be deficient in some patients with schizophrenia, consistent with an interneuron deficit in schizophrenia.

Topics: Antigens, Nuclear; Cerebrum; Female; Humans; Hyperplasia; Interneurons; Male; Middle Aged; Nerve Fibers, Myelinated; Nerve Tissue Proteins; Neuropeptide Y; Prefrontal Cortex; Schizophrenia; Somatostatin

In schizophrenia, glutamic acid decarboxylase 1 (GAD1) disturbances are robust, consistently observed, cell-type specific and represent a core feature of the disease. In addition, neuropeptide Y (NPY), which is a phenotypic marker of a sub-population of GAD1-containing interneurons, has shown reduced expression in the prefrontal cortex in subjects with schizophrenia, suggesting that dysfunction of the NPY+ cortical interneuronal sub-population might be a core feature of this devastating disorder. However, modeling gene expression disturbances in schizophrenia in a cell type-specific manner has been extremely challenging. To more closely mimic these molecular and cellular human post-mortem findings, we generated a transgenic mouse in which we downregulated GAD1 mRNA expression specifically in NPY+ neurons. This novel, cell type-specific in vivo system for reducing gene expression uses a bacterial artificial chromosome (BAC) containing the NPY promoter-enhancer elements, the reporter molecule (eGFP) and a modified intron containing a synthetic microRNA (miRNA) targeted to GAD1. The animals of isogenic strains are generated rapidly, providing a new tool for better understanding the molecular disturbances in the GABAergic system observed in complex neuropsychiatric disorders such as schizophrenia. In the future, because of the small size of the silencing miRNAs combined with our BAC strategy, this method may be modified to allow generation of mice with simultaneous silencing of multiple genes in the same cells with a single construct, and production of splice-variant-specific knockdown animals.

Topics: Alternative Splicing; Animals; Brain Diseases; Chromosomes, Artificial, Bacterial; Disease Models, Animal; Gene Expression Regulation; Gene Silencing; Glutamate Decarboxylase; HEK293 Cells; Humans; Mice; Mice, Transgenic; MicroRNAs; Neuropeptide Y; Schizophrenia

Prefrontal deficits in gamma-aminobutyric acid (GABA)ergic gene expression, including neuropeptide Y (NPY), somatostatin (SST), and parvalbumin (PV) messenger RNAs (mRNAs), have been reported for multiple schizophrenia cohorts. Preclinical models suggest that a subset of these GABAergic markers (NPY/SST) is regulated by brain-derived neurotrophic factor (BDNF), which in turn is under the inhibitory influence of small noncoding RNAs. However, it remains unclear if these mechanisms are important determinants for dysregulated NPY and SST expression in prefrontal cortex (PFC) of subjects with schizophrenia.. Using a postmortem case-control design, the association between BDNF protein, NPY/SST/PV mRNAs, and two BDNF-regulating microRNAs (miR-195 and miR-30a-5p) was determined in samples from the PFC of 20 schizophrenia and 20 control subjects. Complementary studies were conducted in cerebral cortex of mice subjected to antipsychotic treatment or a brain-specific ablation of the Bdnf gene.. Subjects with schizophrenia showed deficits in NPY and PV mRNAs. Within-pair differences in BDNF protein levels showed strong positive correlations with NPY and SST and a robust inverse association with miR-195 levels, which in turn were not affected by antipsychotic treatment or genetic ablation of Bdnf.. Taken together, these results suggest that prefrontal deficits in a subset of GABAergic mRNAs, including NPY, are dependent on the regional supply of BDNF, which in turn is fine-tuned through a microRNA (miRNA)-mediated mechanism.

Topics: Adult; Aged; Aged, 80 and over; Animals; Brain-Derived Neurotrophic Factor; Case-Control Studies; Chromatin; gamma-Aminobutyric Acid; Gene Expression Regulation; Genotype; Humans; Immunoassay; Immunoprecipitation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Middle Aged; Neuropeptide Y; Parvalbumins; Prefrontal Cortex; RNA; Schizophrenia; Somatostatin; Young Adult

It has been suggested that hypoactivity of neuropeptide Y (NPY) may be involved in the pathophysiology of schizophrenia. A post-mortem study revealed a decreased level of NPY in the brain of patients with schizophrenia. An increased level of NPY after antipsychotic treatment was also reported in animal brain and cerebrospinal fluid of patients. Previously Itokawa et al. reported a positive association between the functional -485C>T polymorphism in the NPY gene and schizophrenia in a Japanese population. The aim of this study is to replicate their positive findings in an independent Japanese case-control sample. Our sample includes 260 patients with schizophrenia (DSM-IV) and 196 control subjects. No significant differences in distribution of genotype or allele frequencies between patients and controls were observed. Our results suggest that the NPY -485C>T polymorphism may not confer susceptibility to schizophrenia, at least in our sample. Further studies in larger samples are warranted.

Topics: Adult; Brain; Chi-Square Distribution; Female; Gene Frequency; Genotype; Humans; Japan; Male; Middle Aged; Neuropeptide Y; Polymorphism, Genetic; Postmortem Changes; Promoter Regions, Genetic; Schizophrenia

Topics: Adult; Case-Control Studies; Humans; Korea; Middle Aged; Neuropeptide Y; Polymorphism, Single Nucleotide; Schizophrenia

We examined the hypothesis that -485 T, a novel polymorphism in the promoter region of the neuropeptide Y gene which was shown to be associated with schizophrenia in our previous paper, confers susceptibility to the disease. For a case-control association study, 331 unrelated Japanese schizophrenics (S(1): milder cases in the previous study, n = 212; and S(2): additional severer cases, n = 119) and 199 unrelated normal controls were recruited. Contribution of -485 T to the risk and the severity of the illness was examined by (1) comparing the risk in each genotype in the general population, (2) testing correlations between the gene-dose of -485 T, and the severity of chronic outcome in S(2) assessed with the Positive and Negative Symptom Scale, and (3) comparing the distribution of age at onset in S(1) + S(2) among the three genotypes. -485 T was significantly associated with schizophrenia in S(1) + S(2). Significant negative correlations were observed between the gene-dose and the symptom assessment scores in all items. The homozygote of -485 T showed a second peak frequency in the late-onset group both in males and females, while the homozygote of the alternative allele showed a single peak in the early-onset group. The higher risk of schizophrenia in the heterozygote than in the homozygote of -485 T in the general population did not support the possibility of linkage disequilibrium with a susceptibility gene. -485 T most likely confers resistance but not susceptibility to schizophrenia. An interaction between a nuclear resistance gene and a presumptive pathogenic gene in the mitochondrial DNA was suggested.

Topics: Age Distribution; Age of Onset; Alleles; DNA, Mitochondrial; Female; Gene Dosage; Humans; Japan; Male; Middle Aged; Models, Genetic; Neuropeptide Y; Polymorphism, Single Nucleotide; Schizophrenia

A number of different gene polymorphisms have been found to dispose for the development of schizophrenia. However, no single gene polymorphism is sufficient for the precipitation of schizophrenia. Swedish psychosis patients (n=103) and control subjects (n=89) were analyzed for 36 single nucleotide polymorphisms in 30 candidate genes for schizophrenia. Evidence of association was analyzed with Bayesian statistical methods. Variants in the genes coding for dopamine-D2 receptor, brain-derived neurotrophic factor (BDNF), neuropeptide Y (NPY), neuregulin 1, reelin and synapsin 3 showed association with schizophrenia, although few subjects were found in the minority allele for the two latter variants. The six gene variants, all with suspected connection to schizophrenia, were found to be risk factors when considered in combination, but not separately. The results indicate that the Bayesian statistical method gives additional possibilities in the search for risk factors for schizophrenia or other complex disorders.

Topics: Adult; Alleles; Bayes Theorem; Brain-Derived Neurotrophic Factor; Cell Adhesion Molecules, Neuronal; Chromosome Mapping; Extracellular Matrix Proteins; Female; Genetic Predisposition to Disease; Genetic Variation; Humans; Male; Middle Aged; Nerve Tissue Proteins; Neuregulin-1; Neuropeptide Y; Neuropeptides; Phosphoproteins; Polymorphism, Single Nucleotide; Psychotic Disorders; Receptors, Dopamine D2; Reelin Protein; Risk Factors; Schizophrenia; Serine Endopeptidases; Synapsins

A polymorphism in the promoter region of the NPY gene at position -399 C > T was recently reported to be associated with schizophrenia in a Japanese population and with treatment refractory unipolar depression in a Swedish population. The objective of this study was to investigate potential associations between the polymorphism and three psychiatric disorders in a Danish population.. We investigated the occurrence of the polymorphism in patients with schizophrenia (n = 291), unipolar depression (n = 256) and panic disorder (n = 142) compared with controls (n = 716).. We detected the polymorphism -399 C > T at a frequency of 48% in controls. No significant differences were found between genotype or allele frequencies in controls vs. the patient groups.. The lack of association between the -399 C > T polymorphism and schizophrenia, unipolar depression or panic disorder, respectively, suggests that the polymorphism is not involved in the etiology of these disorders in the Danish population.

Topics: Adult; Aged; Aged, 80 and over; Alleles; Denmark; Depressive Disorder; DNA Primers; Female; Gene Frequency; Genotype; Humans; Incidence; Male; Middle Aged; Neuropeptide Y; Panic Disorder; Polymerase Chain Reaction; Polymorphism, Genetic; Prevalence; Schizophrenia

Clinical researches have shown that there is a genetic contribution to the pathogenesis of schizophrenia. Recent studies have suggested that three genes neuropeptide Y (NPY), phosphoinositide-3-kinase class 3 (PIK3C3) and 14-3-3 eta chain gene (YWHAH) are probably associated with schizophrenia. To replicate these findings, we carried out a family-based study on a sample of 235 trios. Our results suggest that the polymorphisms at the NPY and YWHAH genes are unlikely to be linked with genetic susceptibility to schizophrenia. However, we found significant evidence of preferential transmission of the -432C allele of the PIK3C3 gene in the entire trios (Z=2.91, d.f.=1, P=0.0036) and the male probands trios (Z=2.66, d.f.=1, P=0.0079).

Topics: 14-3-3 Proteins; Adult; Chi-Square Distribution; Family Health; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Male; Neuropeptide Y; Phosphatidylinositol 3-Kinases; Polymorphism, Genetic; Schizophrenia; Sex Factors

A case-control study was carried out on a sample of 583 cases vs. 372 controls in the Chinese Han population, investigating several published polymorphisms in the YWHAH and NPY genes, which reported to be associated with schizophrenia. The polymorphism -134 (GCCTGCA)2-4, in the YWHAH was not analyzed for the failure of amplification, and the polymorphism T1128C in the NPY is not existent in the samples. The analysis was then emphasized on the variants -485C > T(NPY) and G753A(YWHAH). However, no significant differences of allele frequencies (with P values of 0.696 and 0.743, OR values of 1.041 and 0.962 respectively) or genotype frequencies (with P value of 0.45 and 0.75, chi2 = 1.51 and 0.58 respectively) among the matched groups were found. No sex-dependent effect was found either. Also,the analysis of the relative risk between the genotypes of the two genes indicates that the two genes could not cooperate with each other to add the risk of disease (P > 0.05). The results suggest that the polymorphisms - 485C > T (NPY) and G753A (YWHAH) are unlikely to be linked with genetic susceptibility to schizophrenia in the Chinese Han population.

Topics: 14-3-3 Proteins; Asian People; China; Gene Frequency; Genetic Predisposition to Disease; Humans; Neuropeptide Y; Polymorphism, Genetic; Schizophrenia

Topics: Adenosine Triphosphatases; Case-Control Studies; DEAD-box RNA Helicases; Female; Gene Frequency; Humans; Male; Middle Aged; Neuropeptide Y; Oligonucleotide Array Sequence Analysis; Polymorphism, Genetic; Promoter Regions, Genetic; RNA Helicases; RNA, Messenger; Schizophrenia

Hypoactivity of neuropeptide Y (NPY) is thought to be involved in the pathophysiology of schizophrenia, because post-mortem brain studies revealed a decrease of the NPY in schizophrenia, and antipsychotic treatments increase the NPY in animal brains and in cerebrospinal fluid of patients. We performed genetic analysis of the NPY gene in schizophrenia. Mutation screening of the gene detected nine single nucleotide polymorphisms, of which we typed a -485C>T variation from potential functional relevance. The -485T allele was overly represented in the disease group (P=0.0043). An in vitro promoter assay revealed that a C to T change at nt -485 significantly reduced transcriptional activity. These results suggest that the -485T allele in NPY may confer susceptibility to schizophrenia by decreasing the neuropeptide in brains.

Topics: Genetic Predisposition to Disease; Humans; Neuropeptide Y; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Schizophrenia

Quantitative trait locus studies, and observations in animals manipulated for the neuropeptide Y (NPY) gene suggest that variation within this gene may contribute to alcoholism. A recent population study suggested that the Pro7 allele of a functional NPY polymorphism (Leu7Pro) may be associated with increased alcohol consumption. We tested whether the Pro7 allele is associated with alcohol dependence in European Americans (EA).. The design was a population study comparing the Leu7Pro allele frequencies in alcohol-dependent subjects and controls. Population stratification potential and diagnostic specificity was studied by genotyping individuals from additional populations and psychiatric diagnostic classes. We studied 2 independently collected samples of EA alcohol-dependent subjects (sample 1, n = 307; sample 2, n = 160) and a sample of psychiatrically screened EA controls (n = 202); 8 population samples, including African Americans and European Americans (total n = 551); and 4 samples of individuals with Alzheimer disease, schizophrenia, posttraumatic stress disorder, and major depression (total n = 502). The main outcome measure was the difference in Leu7Pro allele frequencies between alcohol-dependent subjects and controls.. The frequency of the Pro7 allele was higher in the alcohol-dependent subjects (sample 1, 5.5%; sample 2, 5.0%) compared with the screened EA controls (2.0%) (sample 1 vs controls, P=.006; sample 2 vs controls, P=.03). The attributable fraction (excess morbidity) in similarly affected populations, owing to the Pro7 allele, was estimated to be 7.3%. The frequency of the Pro7 allele was equal or lower in the population samples, as compared with the screened EA controls (0%-2.2%), with 1 exception (Bedouins). We found no significant evidence that the association of the Pro7 allele with alcohol dependence was due to an association with a comorbid psychiatric disorder.. These results suggest that the NPY Pro7 allele is a risk factor for alcohol dependence. This is only the second specific genetic mechanism ever identified that modulates risk for alcohol dependence.

Topics: Alcohol Drinking; Alcoholism; Black People; Case-Control Studies; Comorbidity; Depressive Disorder; Ethnicity; Europe; Female; Gene Frequency; Genetic Predisposition to Disease; Genetics, Population; Genotype; Humans; Male; Neuropeptide Y; Polymorphism, Genetic; Racial Groups; Schizophrenia; Stress Disorders, Post-Traumatic; United States

Topics: Adult; Autopsy; Brain; Female; Gene Expression; Humans; Male; Middle Aged; Neuropeptide Y; Oligonucleotide Array Sequence Analysis; RNA, Messenger; Schizophrenia

It has been hypothesized that the neuropeptide Y (NPY) system is involved in the pathogenesis of mood disorder. In this study, Y(1) and Y(2) receptor mRNA expression levels were analyzed in the dorsolateral prefrontal cortex of subjects affected with major depression, bipolar disorder, or schizophrenia and compared to normal controls. No significant alterations in Y(1) or Y(2) mRNA expression levels were observed between the groups. However, the Y(2) mRNA expression was elevated in layer IV in subjects with suicide as a cause of death. For the Y(1) mRNA expression, there was a negative correlation with increasing subject age in the prefrontal cortex. Analysis of covariance revealed a significant elevation of the Y(1) mRNA expression levels in individuals with a current history of marijuana use but no other drug. In summary, the current results suggest distinct alterations of the prefrontal Y(1) and Y(2) neuronal populations in aging and suicide.

Topics: Adult; Aged; Aging; Bipolar Disorder; Depressive Disorder, Major; Female; Gene Expression; Humans; Male; Middle Aged; Mood Disorders; Neurons; Neuropeptide Y; Prefrontal Cortex; Receptors, Neuropeptide Y; RNA, Messenger; Schizophrenia; Suicide

1. The authors observed NPY-positive fibers in the CA4 area of the hippocampus from schizophrenics and normal controls using immunohistochemical techniques. 2. Positive fibers followed a straight course and were oriented to exit the CA4 region of hippocampus in normal controls. 3. Many NPY-positive fibers in the CA4 area appeared coiled or helix-like or appeared wasted and thread-like in schizophrenic brains, compared to those of normal controls. 4. These findings may indicate a dysfunction of the interneuron in the schizophrenic brain and support the hypothesis of developmental impairments of the CNS in schizophrenia, and these morphological changes in fibers may relate to schizophrenic symptoms such as memory or/and learning deterioration.

Topics: Aged; Autopsy; Female; Hippocampus; Humans; Immunohistochemistry; Interneurons; Male; Middle Aged; Neuropeptide Y; Schizophrenia

In the present study, we compared neuropeptide Y mRNA expression levels in the prefrontal cortex (Brodmann area 9 and 46) of subjects diagnosed with major depression, bipolar disorder and schizophrenia with those in normal controls without a psychiatric history. No correlation was found regarding neuropeptide Y mRNA expression and postmortem interval, age, gender, hemisphere side, suicide as cause of death, or the history of use of substances such as alcohol, marihuana and cocaine/amphetamine. The only significant alteration found was related to the clinical diagnosis; neuropeptide Y mRNA expression was reduced in the group of bipolar subjects as compared to the controls. Overall, the present results confirm an involvement of neuropeptide Y in affective disorders, and show for the first time a specific association between NPY and bipolar disorder.

Topics: Adult; Aged; Autoradiography; Bipolar Disorder; Depressive Disorder; Female; Humans; In Situ Hybridization; Male; Middle Aged; Neuropeptide Y; Prefrontal Cortex; RNA, Messenger; Schizophrenia; Statistics, Nonparametric

Postmortem investigations were performed in brains from 14 schizophrenic patients and 21 controls matched for age and autopsy latency. Concentrations of galanin, delta-sleep-inducing peptide (DSIP), corticotropin-releasing factor (CRF), arginine vasopressin (AVP), neuropeptide Y (NPY) and peptide YY (PYY) were determined in the hypothalamus and grey matter from the temporal cortex. A significant positive correlation between age and the concentrations of galanin and CRF was found in the controls. No sex differences were found except a higher mean of CRF in the hypothalamus of the women. In the temporal cortex of the schizophrenic brains, galanin, AVP, NPY and PYY were significantly reduced. DSIP reduction only bordered on significance. CRF was not reduced. Comparing neuroleptic-treated vs non-treated schizophrenics, the treatment factor could not explain the reduced concentrations of neuropeptides in the temporal lobe. A comparison of controls with schizophrenics showed no significant differences in hypothalamic neuropeptide concentrations.

Topics: Age Factors; Aged; Aged, 80 and over; Antipsychotic Agents; Arginine Vasopressin; Corticotropin-Releasing Hormone; Delta Sleep-Inducing Peptide; Female; Galanin; Hospitalization; Humans; Hypothalamus; Male; Middle Aged; Neuropeptide Y; Neuropeptides; Peptide YY; Peptides; Schizophrenia; Temporal Lobe

Neuropeptide Y (NPY)-like and peptide YY (PYY)-like immunoreactivities were measured in cerebrospinal fluid (CSF) from patients with major depressive disorder or schizophrenia and from healthy volunteers without physical or mental illness. NPY-like material was significantly lower (P less than 0.001) in CSF of patients with depressive disorders than in schizophrenic patients or healthy controls. Treatment with the antidepressant, amiflamine, a selective MAO-A inhibitor, did not alter CSF peptide concentrations. In drug-free schizophrenic patients, normal NPY but reduced PYY concentrations in CSF were observed. Treatment with neuroleptics did not affect the levels of NPY or PYY in the CSF. The finding of reduced CSF concentrations of NPY in patients with major depression and of reduced PYY concentrations in schizophrenia may reflect disturbed synthesis, turnover or degradation of the peptides. These findings suggest that the reduced concentrations of NPY or PYY in the CSF may be used as trait markers of the respective illnesses.

Topics: Adolescent; Adult; Aged; Depressive Disorder; Female; Humans; Male; Middle Aged; Neuropeptide Y; Peptide YY; Peptides; Radioimmunoassay; Schizophrenia

Although a biochemical abnormality has been postulated in the etiology of schizophrenia, evidence supporting this hypothesis has been conflicting. Because of the presence of somatostatin-like immunoreactivity (SLI) in limbic system nuclei of the brain, we examined postmortem concentrations of SLI in patients dying with schizophrenia and in normal controls. Concentrations of SLI in Brodmann cortical area 38, hippocampus, caudate, putamen, nucleus accumbens, and both segments of the globus pallidus were not significantly different from controls. In addition, we examined both SLI and neuropeptide-Y-like immunoreactivity (NPYLI) in subnuclei of the amygdala and the substantia innominata. There were no significant alterations in either neuropeptide as compared with controls.

Topics: Amygdala; Female; Humans; Male; Middle Aged; Neuropeptide Y; Reference Values; Schizophrenia; Somatostatin

The restriction fragment length polymorphisms (RFLPs) associated with neuropeptide Y (NPY) and somatostatin loci were used to assess the possibility of linkage to a locus for affective disorder (AD). When somatostatin haplotypes were assigned to members of 2 AD pedigrees under either rare dominant or recessive transmission, the LOD scores obtained at 0% recombination were inconsistent with linkage. Similar results were obtained with NPY under rare dominant inheritance. Comparison of the frequency of the genotypes deduced from the polymorphic alleles of gastrin-releasing peptide, NPY, somatostatin and substance P in normals vs patients with either AD or schizophrenia suggests the absence of association. The difference in the frequency of the 3.3 kb adenosine deaminase fragment in normals vs bipolar and schizophrenic patients is of borderline significance.

Topics: Adult; Aged; Bipolar Disorder; Depressive Disorder; Genetic Linkage; Genetic Markers; Humans; Middle Aged; Neuropeptide Y; Neuropeptides; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Risk Factors; Schizophrenia; Somatostatin

Neuropeptide Y (a recently discovered brain peptide that is colocalized with norepinephrine within some adrenergic central nervous system neurons) was measured in the cerebrospinal fluid (CSF) from patients with major affective disorder, chronic schizophrenia, and in normal volunteers. No differences between diagnostic groups were found, suggesting that if this neuropeptide is involved in the pathogenesis of these disorders, an abnormality is not detectable in the CSF.

Topics: Biomarkers; Depressive Disorder; Female; Fluphenazine; Humans; Male; Neuropeptide Y; Reference Values; Schizophrenia

The location of the neuropeptides methionine-enkephalin (ME), neurotensin (NT), neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP) within the amygdaloid complex of healthy human individuals, schizophrenics and patients suffering from Huntington's chorea was studied qualitatively by means of immunohistochemistry. VIP-like immunoreactivity (IR) was present predominantly in a dense cluster of fibers and terminals in the central amygdaloid nucleus. ME-IR was observed in fibers, terminals and cell bodies in the same subnucleus, exhibiting a characteristical distribution pattern. NT-positive cell bodies were situated within the center of the central amygdaloid nucleus, fibers and terminals being encountered mainly at the periphery. NPY-IR was found to be evenly distributed throughout the amygdala. Distribution and staining intensity of ME, NPY and NT in the amygdala showed no qualitatively recognizable difference between the normal and schizophrenic specimens, whereas VIP-IR appeared to be slightly increased in the central amygdaloid nucleus of schizophrenics. In the choreic cases, the considerably shrunken amygdala exhibited only very low staining intensity of the four investigated neuropeptides.

Topics: Adult; Aged; Amygdala; Enkephalin, Methionine; Female; Humans; Huntington Disease; Immunoenzyme Techniques; Male; Middle Aged; Neuropeptide Y; Neuropeptides; Neurotensin; Schizophrenia; Vasoactive Intestinal Peptide