اساس مولکولی اسکیزوفرنی

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SCHIZOPHRENIA By : Behnaz Bazrafs' PhD Student in Molecular ‘medi icine 

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What is schizophrenia? ABNORMAL PS¥CHOL: ‏ام ول‎ PerspectivesigmsPaycholoxical Disoy 

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Schizein + Phren=Schizophrenia © The broad category of schizophrenia includes a set of disorders in which individuals experience distorted perception of reality and impairment in thinking, behavior, affect, and motivation. 

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Symptoms of schizophrenia Positive symptoms: Negative symptoms: Exaggerations or distortions of | Symptoms that involve normal thoughts, emotions, and functioning below the level of behavior normal behavior 

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Symptoms of schizophrenia Reser 1 | = Delusions * Restricted affect * Hallucinations * Avolition = Disorganized speech = A-sociality " Disturbed behavior 

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Type of Schizophrenia ۹ Le Paranoid Schizophrenia 

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Catatonic Schizophrenia 

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Disorganized Schizophrenia (Hebephrenia) 

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Undifferentiated Schizophrenia 

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Residual Schizophrenia Residual schizophrenia is a type of schizophrenia where a person displays mostly the negative symptoms of schizophrenia. To understand this type of schizophrenia, it is important to understand the difference between positive and negative symptoms of schizophrenia. 

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STATISTICS ° Schizophrenia affects slightly more males than females. ° For every three men who develop schizophrenia over the course of their lives, two women are affected with the disorder. ° affecting 0.5-1% of the population in early adulthood. ° Researchers estimate the lifetime prevalence as about 5% and the prevalence at any one time of about 3%. ° People with schizophrenia are two to three times more likely to die compared to others within their age group. ° Annual incidence is 15-20 per 100,000 

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Age and circumstances of onset Peak age of onset for men is 17-30 Peak age of onset for women is 20-40 

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Courses of Schizophrenia °Continuous °Remission °Recurrent oFxtended 

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Theories °1. Dopamin Hypothesis °2. Neuroanatomical °3.Genetics 

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Dopamine Hypothesis of Schizophrenia Model for dopamine involvement °Increased subcortical dopamine activity °Decreased prefrontal dopamine activity 

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Risk Factor For Schizophrenia Eat paola tae titer EP = 11191۹ 119 Previous drug ‏امومع‎ 

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These Factors May Double or Triple the Risk Maternal medical conditions: Childhood / adolescence pre-eclampsia, diabetes Cannabis Prenatal Exposures: Traumatic brain injury infection (influenza, rubella) Trauma, loss, stress Malnutrition Environmental Exposure: stress (war, flood) Meee Rh incompatibility Lead Exposure Season of Birth Dry cleaning PERC Obstetric complications: especially hypoxia low birth weight preterm birth Genetics: From Genetic Studies Copy number variations New mutations 

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۰ ‏جيم‎ Genetic Evidence 

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Genetic or Biological Causes of ك2 —— SAURABH SUMAN — ruc nates 10, 204 Strong genetic component to ae schizophrenia Gonad anavoa = 17.5% Gnird-degree Pesan) Neo (or distant) relat 2596 (second-degree relatives) Note that even identical twins are not 100% eres concordant relatives) ie. genetics ore not Fhe whole story 

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Nuerotransmitters 

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Dopamine is an organic chemical of the catecholamine and phenethylamine families ۳ we HO It functions both as a hormone and a neurotransmitter It is an amine synthesized by removing a carboxyl group from a molecule of its precursor chemical L-DOPA, which is synthesized in the brain and kidneys. Dopamine plays a role in how we feel pleasure, ability to think and plan. It helps us strive, focus, ar + ngs interesting. he Rerward Hormone COPAMINE idl 9 

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Serotonin or 5-hydroxytryptamine ۷۳2 1: : HO. * monoamine neurotransmitter \ + In humans, present in GI enterochromaffin cells N (90%), platelets and brain. H + Synthesized from tryptophan (in diet) in two steps. SEROTONIN + This hormone (and neurotransmitter) helps regulate your mood as well as your sleep, appetite, digestion, learning ability, and memory. Decreased levels of 5-hydroxyindoleacetic acid in cerebrospinal fluid have been found to be correlated The Will- Power Hormone with cortical atrophy or ventricular enlargement in schizophrenic patients. Schizophr Bull. 1988;14(2):297-315. Happiness hormone 

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Norepinephrin Or Noradrenalin FIGHT or FLIGHT Concentrating Neurotransmitter and Hormone OH 

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Format: Abstract ~ Send to~ Psychiatry Res, 2014 Mar 30;215(3):497-504. doi: 10.1016/}.psychres.2014.01.011. Epub 2014 Jan 18. Is elevated norepinephrine an etiological factor in some cases of schizophrenia? Fitzgerald Put © Author information 1 Department of Psychology, Texas A&M University, College Station, Room 3200 ILSB, TX 77843-4236, USA. Electronic address pfitz@mbi.mb jhu.edu. Abstract Anumber of hypotheses have been put forth regarding the etiology of schizophrenia, including the dopamine hypothesis, NMDA receptor hypofunction hypothesis, and others. A lesser known theory is that elevated noradrenergic signaling plays a causative role in the disease. This paper briefly re-examines the merits of this hypothesis, including as it relates to some recently published studies. Several lines of evidence are investigated, including: endogenous level studies of norepinephrine (NE); modulation of the disease by noradrenergic drugs; association of the disease with bipolar disorder and hypertension, since these latter two conditions may involve elevated NE transmission; and effects of psychological stress on the disease, since stress can produce elevated release of NE. For many of these lines of evidence, their relationship with prepulse inhibition of startle is examined. A number of these studies support the hypothesis, and several suggest that elevated NE signaling plays a particularly prominent role in the paranoid subtype of schizophrenia. If the hypothesis is correct for some persons, conventional pharmaceutical treatment options, such as use of atypical antipsychotics (which may themselves modulate noradrenergic signaling), may be 

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Results of this Paper ° effects of psychological stress on the disease, since stress can produce elevated release of NE. For many of these lines of evidence, their relationship with prepulse inhibition of startle is examined. A number of these studies support the hypothesis, and several suggest that elevated NE signaling plays a particularly prominent role in the paranoid subtype of schizophrenia. 

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Acetylcholine 0 \/ Learning Neurotransmitter Reduced acetylcholine 

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9 GABA 0 تلان حم وب Calming Neurotransmitter 

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# frontiers seven in Psychiatry nea GABAergic Mechanisms in Schizophrenia: Linking Postmortem and /n Vivo Studies Jeroen C. de Jonge’, Christiaan H. Vinkers', Hilleke E. Hulshoff Pol! and Anouk Marsman'* 2 Bran Center Rudo Magnus, Department of Psychiaiy. Unersty Medical Center Utrecht, Utrecht, Nexans, *Banisn Ressarch Centre for Magnetic Resonance, Cepenhagen University Hospital Hvdove, Huisoure, Denmarie Schizophrenia is a psychiatric disorder characterized by hallucinations, delusions, disorganized thinking, and impairments in cognitive functioning. Evidence from post- mortem studies suggests that alterations in cortical y-aminobutyric acid (GABAergic) neurons contribute to the clinical features of schizophrenia. in vivo measurement of brain GABA levels using magnetic resonance spectroscopy (MRS) offers the possibility OPEN ACCESS to provide more insight into the relationship between problems in GABAergic neuro- Edited by: transmission and clinical symptoms of schizophrenia patients. This study reviews and ‎ae Stim links alterations in the GABA system in postmortem studies, animal models, and human‏ ریز 

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Comments Schizophrenia, bipolar clisorcer, and major depression GADG7 protein unaltered in chandelier Findings: GADE7 mRNA 1 (OFS, caudate, nucleus accumbens) 7عصمه ‎MRNA 1‏ ‎Gape7‏ ‎mRNA 4‏ 7عصمه ‎protein 1‏ ‎GADe7‏ ‎mRNA 1‏ ‎GADes‏ ‎mRNA‏ ‏7عصمه ‎protein 1‏ TABLE 4 | Continued Brain region AGG (BA24) Orbital frontal cortex (OFC) (BA45) STG (BA22) Caudate Putamen Nucleus accumbens Medial dorsal thalamus: Anterior thalamus. DLPFC (Ba9/46) معصاه DLPFC (BAS) DLPFC (BAS) DLPFC (BAS) Reference Thompson etal. (3) Dunean etal. (17) Curley et al. (4) Kioto, etal. (22) Glausier et al. (40) Rocco etal. (31) 

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TABLE 2 | Postmortem studies on GABA transporters (GAT)-1 in schizophrenia. Findings GAT-1-IR cartridges of chandelier neurons | GAT-1-IR cartridges of chandelier neurons 1 ‎mRNA |‏ دی ‎GAT mRNA |‏ ‎GAT-+-IR cartridges of‏ ‎chandelier neurons =‏ ‎mRNA ۲‏ نمی ‎GAT-1 mRNA |‏ ‎Brain region ‎Dorsolateral prefrontal cortex (DLPFC) (BAQ) ‎DLPFC (BA46) ‎DLPFC (BA9/10) DLPFC (BAQ) ‎Auditory association area (BA42) ‎DLPFC (BAQ) ‎DLPFC (BAQ) ‎Anterior cingulate cortex (BA24) ‎Primary visual cortex Primary motor cortex ‎Reference ‎Woo et al. (65) Pierri et al. (66) ‎Ohnuma et al. (64) Volk et al. (59) Konopaske et al. (62) ‎Hashimoto et al. (20) Hashimoto et al. (21) ‎ 

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Molecular Pathology Journal List » HHS Author Manuscripts > PMC3319053 sé HHS Public Access aa Author manuscript Peer-revis nd accepted for publication خاما كن مدي ‎EET‏ م Neuroimage. Author manuscript; available in PMC 2013 Jan 2. PMCID: PMC3319053 NIHMSID: NIHMS313052 PMID: 21787868 Published in final edited form as: Neuroimage. 2012 Jan 2: 59(1): 154- Published online 2011 Jul 20. doi: 10.1016 /j, neurcimage.2011,.07.0114 Study Factors Influencing Ventricular Enlargement in Schizophrenia: A 20 Year Follow-Up Meta-Analysis Angelo Saye, Robin G, Jennings, and John Darrell Van Hom” » Author information + Copyright and License information Disclaimer The niiblicher's final edited varsion af this article is available at Natirnimane 

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Increased ventricular size relative to controls Disruption of Neural cells Men has more larger ventricular size 

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Gray Mater loss in schizophrenia = Gray Matter redticed in schizophrenic people in frontal cortex ° Cortex have a crucial role in speech,make decision and behavior 

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Hippocampus 1.Navigation 2.Emotions 3.Learning 4.memories 

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OPEN Molecular Psychiatry (2016) 21, 547-553 © 2016 Macmillan Publishers Limited All rights served 1359-4184/16 www.nature.comimp ORIGINAL ARTICLE Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium TGM van Erp'®, DP Hibar*2®, JM Rasmussen, DC Glahn?4, GD Pearlson**, OA Andreassen®, | Agartz*?, LT Westlye™®, UK Haukvik®, AM Dale”°, | Melle®, CB Hartberg**, O Gruber'', B Kraemer'', D Zilles'"'?, G Donohoe'*"*, § Kelly?"*, C McDonald", DW Morris'*"*, DM Cannon", A Corvin'*, MWJ Machielsen'®, L Koenders'®, L de Haan'®, DJ Veltman’, TD Satterthwaite'*, DH Wolf'®, RC Gur" RE Gur", SG Potkin', DH Mathalon"?°°, BA Mueller”, A Preda’, F Macciardi’, S Ehlich**"*"*, E Walton”, J Hass”, VD Cathoun”®"*, HJ Bockholt”°77®, SR Sponheim7”, JM Shoemaker?*, NEM van Haren®°, HEH Pol?°, RA Ophoff??", RS Kahn*®, R Roiz-Santiahez???, B Crespo-Facorro™?##, L Wang**"*, KI Alpert®*, EG Jonsson*”, R Dimitrova*®, C Bois®®, HC Whalley**, AM Mcintosh®®, SM Lawrie?®, R Hashimoto”, PM Thompson® and JA Turner" for the ENIGMA Schizophrenia Working Group“ The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We Identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen's d=~ 0.46), amygdala (d= 0.31), thalamus (d=— 0.31), accumbens (d=— 0.25) and intracranial volumes (d=~0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d= 0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe 

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۱۴۸ 3 US National Library of Medicine Notional Institutes of Hoan Advanced — Journal list Journal List » Schizophr Bull > v.41(1); 2015 Jan > PMC4266285 Sohizophr Bull. 2015 Jan; 41(1): 233-249. PMCID: PMC4266285 Published online 2014 Feb 20. doi: 10.1093/schbul/sbu009 PMID: 24557771 Hippocampal Volume Is Reduced in Schizophrenia and Schizoaffective Disorder But Not in Psychotic Bipolar | Disorder Demonstrated by Both Manual Tracing and Automated Parcellation (FreeSurfer) Sara J. M. Amold, 1 Elena 1. Ivieva,” 1 Tejas A. Gopal, 1 Anil P. Reddy, 1 Haekyung Jeon-Slaughter, 1 Carolyn B. Sacco, ' Alan N. Francis, ? Neeraj Tandon, 2 Anup S. Bidesi, 1 Bradley Witte, * Gaurav Poudyal, 1 Godfrey D. Pearison, 3 John A. Sweeney, ' Brett A. Clementz, 4 Matcheri S. Keshavan, ? and Carol A. Tamminga تباصا وا * Author information » Copyright and License information Disclal 

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Results °FreeSurfer measurements showed reduced hippocampal volumes in SZ and SAD compared with BDP 

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Arch Gen Psychiatry, 1998 May;55(5):433-40. lippocampal volume reduction in schizophrenia as assessed by magnetic resonance imaging: a meta-analytic study. Nelson MD", Saykin AJ, Flashman LA, Riordan HJ. © Author information 1 Department of Psychology, Dartmouth College, Hanover, NH, USA, Abstract BACKGROUND: Although many quantitative magnetic resonance imaging studies have found significant volume reductions in the hippocampi of patients with schizophrenia compared with those of normal control subjects, others have not. Therefore, the issue of hippocampal volume differences associated with schizophrenia remains in question. METHODS: Two meta-analyses were conducted to reduce the potential effects of sampling error and methodological differences in data acquisition and analysis. Eighteen studies with a total patient number of 522 and a total control number of 426 met the initial selection criteria. RESULTS: Meta-analysis 1 yielded mean effect sizes of 0.37 (P<.001) for the left hippocampus and 0.39 (P<.001) for the right, corresponding to a bilateral reduction of 4%. Meta-analysis 2 indicated that the inclusion of the amygdala in the region of interest significantly increased effect sizes across studies (effect size for the left hippocampus and amygdala, 0.67; for the right, 0.72), whereas variables such as illness duration, total slice width, magnet strength, the use of the intracranial volume as a covariate, measurement reliability, and study quality did not. No laterality differences were observed in these data. CONCLUSIONS: Schizophrenia is associated with a bilateral volumetric reduction of the hippocampus and probably of the amygdala as well. These findings reinforce the importance of the medial temporal region in schizophrenia and are consistent with frequently reported memory deficits in these patients. Future quantitative magnetic resonance imaging studies evaluating the hippocampal volume should measure the hippocampus and amygdala separately and compare the volumetric reduction in these structures to that observed in other gray matter areas. 

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BACKGROUND: ° Although many quantitative magnetic resonance imaging studies have found significant volume reductions in the hippocampi of patients with schizophrenia compared with those of normal control subjects, others have not. Therefore, the issue of hippocampal volume differences associated with schizophrenia remains in question. METHODS: ° Two meta-analyses were conducted to reduce the potential effects of sampling error and methodological differences in data acquisition and analysis. Eighteen studies with a total patient number of 522 and a total control number of 426 met the initial selection criteria. ° RESULTS: Meta-analysis 1 yielded mean effect sizes of 0.37 (P<.001) for the left hippocampus and 0.39 (P<.001) for the right, corresponding to a bilateral reduction of 4%. Meta-analysis 2 indicated that the inclusion of the amygdala in the region of interest significantly increased effect sizes across studies (effect size for the left hippocampus and amygdala, 0.67; for the right, 0.72), whereas variables such as illness duration, total slice width, magnet strength, the use of the intracranial volume as a covariate, measurement reliability, and study quality did not. No laterality differences were observed in these data. CONCLUSIONS: ° Schizophrenia is associated with a bilateral volumetric reduction of the hippocampus and probably of the amygdala as well. These findings reinforce the importance of the medial temporal region in schizophrenia and are consistent with frequently reported memory deficits in these patients. Future quantitative magnetic resonance imaging studies evaluating the hippocampal volume should measure the hippocampus and amygdala separately and compare the volumetric reduction in these structures to that observed in other gray matter areas. 

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HHS Public Access ۳ Author manuscript Psychiatry Res, Author manuscript; available in PMC 2017 April 30. Published in final edited form a= Paychiauty Res 2016 Aptil 30; 250; 50-60. doi:10.10161) pseyehresns.2016.02,006, early course schizophrenia Amygdala volume is reduced Alyson M. Rich®!?, Youngsun T, Cho®.', Yanging Tang?, Aleksandar Savic®, John H. Krystal2te, Fei Wang, Ke Xu", and Alan Anticevic?®4..a." *Department of Psychiatry, Yale University School of Medicine, 300 George Street, New Haven, eT 06511, USA “Department of Psychiatry, The First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning, PR Chine University Psychiatric Hospital Vrapce, University of Zagreb, Zagreb 10000, Cro: “Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT 06519, ‏مون‎ °NIAAA Center for the Translational Neuroscience of Alcoholism, New Haven, CT 06519, USA ‘Department of Radiology, The First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning, PR China ‘SDepartment of Psychology, Yale University, 2 Hillhouse Avenue, CT 06520, USA hInterdepartmental Neuroscience Program, Yale University, New Haven, CT 08520, USA ‘College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, MI, 48108, USA Abstract Subcortical structural alterations have been implicated in the neuropathology of schizophrenia. ‏ی‎ ses ‏ات یقت رپ مس سای ی تسام رس ی موز ای ی‎ Mace oa ube Aaa Cesena a, dhosnueyy soury yduosrueyy souiny 1/9/۷۷ 

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Results © This study demonstrated smaller amygdala volumetric ratios among patients with early-course schizophrenia relative to other groups. While other subcortical structures were examined, no significant group differences in the volumes of the thalamus, nucleus accumbens, putamen, globus pallidus or hippocampus were found. 

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Frontal Lobe Frontal Lobe: Premotor area__—5 

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Frontal Lobe Function 

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Molecular Genetics reg 

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Negative Selection ° An interesting, though not unexpected, observation is that patients with schizophrenia have significantly fewer children compared to the general population . °In theory, this should be generating an enormous negative selective pressure quickly removing risk alleles from the population; however, the disease maintains a relatively high heritability and prevalence at ~1%. » Among possible explanations are balancing selection favoring genotype diversity; advantage for those who carry the allele but do not get sick; changing environments that expose or protect cryptic variation; or quick replenishment by new mutations, in view of the possibility that disruption of thousands of different genes may be able to lead to disease . 

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Molecular Mechanism and Genes © 5HT2 gene ° DTNBP1 ° NGR1 ° COMT 5 51 

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SHT2RA 5-Hydroxytryptamine (Serotonin) Receptor 2A, G Protein-Coupled Cytogenetic band:13q14.2 Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5- dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD) (PubMed:28129538). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways 

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DTNBP1 © Cytogenetic Location: 6p22.3 ° encodes dysbindin-1 Protein © Dysbindin-1 is enriched in the dorsolateral prefrontal cortex and hippocampus, while postmortem brain studies of individuals with schizophrenia show decreased levels of dysbindin-1 mRNA and protein in these brain regions. 

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International Jounal of S| Molecular Sciences (mbpy Dysbindin-1 Involvement in the Etiology of Schizophrenia Haitao Wang *, Jiangping Xu !, Philip Lazarovici ? and Wenhua Zheng >+* 1 Department of Neuropharmacology and Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; wht821@smu.edu.cn (H.W.); jpx@smuedu.cn .X.) School of Pharmacy Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel; philipl@ekmad.hujiac.il Faculty of Health Sciences, University of Macau, Taipa, Macau 999078, China Zhuhai UM Science & Technology Research Institute, Zhuhai 519080, China * Correspondence: wenhuazheng@umac.mo; Tel.: +00853-8822-4919 Received: 28 August 2017; Accepted: 19 September 2017; Published: 22 September 2017 about 1% of the world’s 3 disability. Existing therapeutic strategies have had limited success on cognitive impairment and long-term disability and are burdened by side effects. Although new antipsychotic medications have been launched in the past decades, there has been a general lack of significant innovation. This lack of significant progress in the pharmacotherapy a reflection of the complexity and heterogeneity of the disease. To date, many susceptibility genes have been identified to be associated with schizophrenia. DTNBP1 gene, which encodes dysbindin-1, has been linked to schizophrenia in multiple populations. Studies on genetic variations show that DTNBP! modulate prefrontal brain functions and psychiatric phenotypes. Dysbindin-1 is enriched in the dorsolateral prefrontal cortex and hippocampus, while postmortem brain studies .of inafividuals wilh schizophrenia uhow- decreased levels af dysbindiied iniRNAand. disorder that affli Abstract: Schizophrenia is a major psychiatri population, falling into the top 10 medical disorders cau of schizophrenia 

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Dysbindin-1 in Schizophrenia Dysbindin-1 protein was localized at both pre- and post-synaptic sites, where it regulates neurotransmitter release and receptors signaling. Moreover, dysbindin-1 has also been found to be involved in neuronal development. Is a part of Biogenesis of lysosome-related organelles complex 1(BLOC) , BLOC-1 is required for normal biogenesis of specialized organelles of the endosomal-lysosomal system, such as melanosomes and platelet. dense granules. Reduced expression levels of dysbindin-1 mRNA and protein appear to be common in dysfunctional brain areas of schizophrenic patients. dysbindin is found in neural tissue of the brain, particularly in axon bundles and especially in certain axon terminals, notably mossy fiber synaptic terminals in the cerebellum and hippocampus. 

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Neuregulin 1 © Neuregulin-1 (NRG1J) is vital for neurodevelopment and plasticity. ° Schizophr Res. 2010 Dec;124(1-3):200-7. doi: 10.1016/j.schres.2010.09.001. ° Decreased Neuregulin 1 C-terminal fragment in Brodmann's area 6 of patients with schizophrenia. 

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COMT ‘The COMT gene is 27.22kb in length, and is located on chromosome 22q11.2 There are two isoforms expressed from two promoters, the soluble S-COMT isoform that is expressed in most tissues, such as liver, blood, and kidneys, and the membrane-bound form MB-COMT that is more common in the brain. » The MB-COMT form is of particular interest because of its role in regulating extracellular dopamine levels in the prefrontal cortex. an enzyme that inactivates the neurotransmitter dopamine. * SNP: Val158Met in aggressive behavior. involved in the methylation and degradation of the catecholamine neurotransmitters dopamine, epinephrine, and norepinephrine. The several allelic variants of COMT affect its activity. Microdeletion COMT was observed in schizophrenic patient 

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DISC1 Disrupted in schizophrenia 1 © Chromosome 1442.1 » involved in several processes that regulate sours! development! and brain maturation such as neuronal proliferation, differentiation, migration, cAMP signaling, cytoskeletal modulation, and translational regulation via various signaling pathways. © Expression profile is highest in the hippocampus during development and remains highly expressed in the adult dentate gyrus and ol{aclory bull, regions where adult neurogenesis is present. ° overexpressed human DISC1 

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Beta-carotene Anthccekant Def Systems Gta. snr, Homer tie Cell Survival ‘Cell Proliferation Neurogenesis 2 PRK Ake م 2-0 1 Diverse functions سيت 12 ‘Degradation, DNA Pragmentarion ER Stress, Death Receptor Pathways ane ‏شوك‎ a GABA cS Neurotransmitters orn 4 em Metabotropic Receptors Glutamate مهم ها ۳ Receptors Tyas Sigal DARPP-32 Proapeptotie ] 451-30 [ ‏حب‎ fax 3 ۲ ۷ ye oe 1 ‏هل‎ ‏ع3‎ | rat ‏لعجتمسم) عدم‎ Ay 2 ‏ها‎ Caspases Te ‏عمطت‎ Net eg. BDNF تس 

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Hoseth et al, Translational Psychiatry 2018855 DOI 10.1038/s41 398-018.0102-1 Translational Psychiatry Cees Open Access Exploring the Wnt signaling pathway in schizophrenia and bipolar disorder Eva Z. Hoseth®™, Florian Krull’, Ingrid Dieset’, Ragni H. Merch’, Sigrun Hope’, Erlend S. Gardsjord'', Nils Eiel Steen’, Ingrid Melle', Hans-Richard Brattbakk*”, Vidar M. Steen*®, Pal Aukrust®”®°, Srdjan Djurovic'®", Ole A. Andreassen@! and Thor Ueland***'* Abstract The Wht signaling pathway plays a crucial role in neurodevelopment and in regulating the function and structure of the adult nervous system. Schizophrenia (SCZ) and bipolar disarder (BD) are severe mental disorders with evidence of subtle neurodevelopmental, structural and functional neuronal abnormalities. We aimed to elucidate the role of aberrant regulation of the Wnt system in these disorders by evaluating plasma levels of secreted Wnt modulators in patients (SCZ = 551 and BD = 246) and healthy controls (HCs = 639) using enzyme immune-assay. We also investigated the expression of 141 Wnt-related genes in whole blood in a subsample (SCZ = 338, BD = 241, and HCs = 263) using microarray analysis, Both SCZ and BD had dysregulated mRNA expression of Wnt-related genes favoring attenuated canonical (beta-catenin-dependent) signaling, and there were also indices of enhanced non-canonical Wnt signaling. In particular, FZD7, which may activate all Wnt pathways, but favors non-canonical signaling, and NFATC3, a downstream transcription factor and readout of the non-canonical Wnt/Ca** pathway, were significantly increased in SCZ and BD (p < 3 x 10-). Furthermore, patients had lower plasma levels of soluble dickkopf 1 and sclerostin (p < 0.01) compared with HC. Our findings suggest that SCZ and BD are characterized by abnormal Wnt gene expression and plasma protein levels, and we propose that drugs targeting the Wnt pathway may have a role in the treatment of severe mental disorders. 

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The Wnt signaling pathway ° Plays a crucial role in neurodevelopment ° Regulating the function and structure of the adult nervous system ° The three best characterized Wnt signaling pathways 1. canonical Wnt pathway(Wnt/B-catenin pathway), 2. the noncanonical planar cell polarity pathway, 3. and the noncanonical Wnt/calcium pathway. 

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Wnt/p-catenin Woy Pathway Ca2+Pathway 

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Differences in Wnt pathway gene expression between patients with schizophrenia spectrum disorder and healthy controls after controlling for age, gender, and SIGNALING PATHWAY Decrease Increase SCHIZOPHRENIA vs. CONTROLS| —p<0.05 [EURUE! ‏0.55>م‎ 228220 CYTOPLASM EXTRA CELLULAR SFRP3 DKK2 FRP2 WNT10A —> - LRP5/6 [ssost ‏تسد‎ 237 27 Canonical pathway § > Siah-2 3 ps3 - - > B-catenin degradation ‏اجب هط دق‎ 86612 ——————> Cytoskeletal change ‎Gene transcription‏ >—————— ور و ‎RACAL‏ ‏تا بر ‎MES‏ > :د < ‏الكفنة بت ‏م2۳ ‏جح تا >— ‎WNT1‏ ‎Non-canonical ‎PCP pathway ‎ ‎ ‎ ‎WNTs| —> - > PLCBL ‎Non-canonical ‎Wnt/Ca2+ pathway’ ‎ 

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Results are given as p-values where significant results (p-values adjusted for multiple testing) are indicated in red/dark blue (for increased/decreased mRNA expression) and nominally significant results (0.001 < p < 0.05) are shown as pinis/light blue (for increased/decreased mRNA expression). The figure summarizes relevant genes for the three Wnt pathways (i.e., canonical pathway, non-canonical planar cell polarity pathway, and the non-canonical Wnt/Ca2+ pathway). The figure is based on the Wnt signaling pathway in the KEGG database 

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Treatment Okbrprvwatee (OPT) 1.is an antipsychotic medication 2. used to treat psychotic disorders such as ۱۳۵۵ ١ schizophrenia ChlorproMAZINE Hydrochloride Tablets, USP 3. Chlorpromazine acts as an antagonist (blocking agent im - Beaty 00 مه( on different postsynaptic and presynaptic receptors: 

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Dopamine receptors (subtypes D,, D,, D, and D,), which account for its different antipsychotic properties on productive and unproductive symptoms, in the mesolimbic dopamine system accounts for the antipsychotic effect whereas the blockade in the nigrostriatal system produces the extrapyramidal effects Serotonin receptors (5-HT,, 5-HT, and 5-HT,), with anxiolytic, antidepressant and antiaggressive properties as well as an attenuation of extrapyramidal side effects, but also leading to weight gain and ejaculation difficulties. Histamine receptors (H, receptors, accounting for sedation, antiemetic effect, vertigo, and weight gain) o,- and o adrenergic receptors (accounting for sympatholytic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism—controversial. Also associated with weight gain as a result of blockage of the adrenergic alpha 1 receptor) M, and M, muscarinic acetylcholine receptors (causing anticholinergic symptoms such as dry mouth, blurred vision, constipation, difficulty or inability to urinate, sinus tachycardia, electrocardiographic changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side effects). 

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John Forbes Nash Jr. June 13, 1928 - May 23, 2015 (1994) (1996) (2015) A film by a true sto: 

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"I Am Not a Monster: Schizophrenia“ Campain Astronomer McGough suffers from severe schizophrenia. 

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Elyn Saks Professor of Law, Psychology, and Psychiatry and the Behavioral Sciences at the University of Southern California Gould Law School, an expert in mental health law and a MacArthur Foundation Fellowship winner. 

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