Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Allele and haplotype frequencies of a promoter polymorphism in the gene encoding tryptophan hydroxylase (TPH2) did not differ in 83 suicidal schizophrenic patients compared with 170 non-suicidal schizophrenic patients. These findings suggest that these 5' marker haplotypes in the TPH2 gene do not influence suicidal behavior in schizophrenia.
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PMID:Promoter polymorphism of second tryptophan hydroxylase isoform (TPH2) in schizophrenia and suicidality. 1584 Apr 21

The tryptophan hydroxylase isoform-2 gene (Tph2) is located on chromosome 12 and is expressed primarily in brain tissue. Although the tryptophan hydroxylase isoform-1 gene (Tph1) has been reported to have a genetic association with bipolar disorder and schizophrenia, the Tph1 isoform is expressed at much lower levels than Tph2 (150-fold less in the mouse brain). We hypothesized that bipolar disorder and schizophrenia are associated with abnormal levels of TPH2 mRNA in the brain. TPH2 and beta-actin mRNA levels in postmortem brain were quantified using real-time PCR. mRNA samples provided by the Stanley Foundation Array Collection were derived from the dorsolateral prefrontal cortex (Brodmann Area 46) of 35 bipolar, 35 schizophrenic, and 35 control subjects. There were significant differences in the mRNA levels among bipolar, schizophrenic, and normal subjects [F(2,102)=3.58; p=0.031]. A greater amount of TPH2 mRNA was found in the bipolar group in comparison with control subjects (Tukey's test: p=0.024). Further investigations of Tph2 are needed to clarify the potential role of this gene in the pathophysiology of bipolar disorder.
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PMID:Tryptophan hydroxylase 2 gene expression and promoter polymorphisms in bipolar disorder and schizophrenia. 1624 Jan 63

Suicide is a major public health issue, especially in western countries, accounting for approximately 1 million deaths every year throughout the world. The tryptophan hydroxylase (TPH) gene has been extensively studied as a candidate for suicidal behavior due to its role in serotonergic neurotransmission. Since the first study associating the gene with schizophrenia, there have been many attempts to replicate it. However, a number of these studies have produced contrary results, possibly reflecting inadequate statistical power and the use of different populations. Association data relating European and, more particularly, Asian populations has become increasingly available in recent years. To examine whether the aggregate data provide evidence of statistical significance, the current meta-analysis has combined all the published studies up to July 2005, and examined the polymorphisms (A779C, A218C, A-6526G) in the context of varied suicidal behaviors by analyzing the studies in total and in subsets. Compared with the inconsistent results of previous studies, the current results (22 references) confirm a strong overall association between suicidal behavior and the A779C/A218C polymorphisms, supporting the involvement of TPH in the pathogenesis of suicidal behavior.
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PMID:Further clarification of the contribution of the tryptophan hydroxylase (TPH) gene to suicidal behavior using systematic allelic and genotypic meta-analyses. 1645 Jan 14

A number of studies have suggested an association between schizophrenia and the tryptophan hydroxylase (TPH) and tyrosine hydroxylase (TH) genes. On the other hand, several studies attempting to replicate these findings have produced mixed results, possibly reflecting inadequate statistical power of the individual studies as well as the heterogeneity inherent in schizophrenia. In an attempt to clarify this inconsistency our meta-analysis has combined all the studies using multiple research methods published up to February 2006 to give a comprehensive picture of the role of three hydroxylase-related genes. The TPH A218C/A779C (OR = 1.18, 95% C.I. 1.06-1.33, P = 0.004) revealed a significant association with schizophrenia. However, the evidence for the TH and phenylalanine hydroxylase (PAH) genes was weak. No publication bias was detected in current studies. The findings, which may implicate the involvement of TPH in the pathogenesis of schizophrenia, have potentially important clinical, scientific and public health implications as well as providing a putative basis for the study of hydroxylase-related drugs. To our knowledge, this is the first meta-analysis of association between the three genes and schizophrenia.
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PMID:Meta-analysis shows association between the tryptophan hydroxylase (TPH) gene and schizophrenia. 1765 77

Deficits in sensorimotor gating, a function to focus on the most salient stimulus, could lead to a breakdown of cognitive integrity, and could reflect the "flooding" by sensory overload and cognitive fragmentation seen in schizophrenia. Sensorimotor gating emerges at infancy, and matures during childhood. The mechanisms that underlie its development are largely unclear. Here, we screened the mouse genome, and found that tryptophan hydroxylase (TPH) is implicated in the maturation of sensorimotor gating. TPH, an enzyme involved in the biosynthesis of serotonin, proved to be required only during the weaning period for maturation of sensorimotor gating, but was dispensable for its emergence. Proper serotonin levels during development underlie the mature functional architecture for sensorimotor gating via appropriate actin polymerization. Thus, maintaining proper serotonin levels during childhood may be important for mature sensorimotor gating in adulthood.
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PMID:Requirement of tryptophan hydroxylase during development for maturation of sensorimotor gating. 1697 84

While many studies suggest an involvement of brain serotonergic systems in neuro-psychiatric disorders such as schizophrenia and depression, their role in Wernicke-Korsakoff syndrome (WKS) remains unclear. Since dietary thiamine deficiency (TD) in mice is considered as a putative model of WKS, it was used in the present study to investigate the function of serotonergic neurons in this disorder. After 20 days of TD feeding, the intensity of tryptophan hydroxylase immunofluorescence was found to be significantly decreased in the dorsal and medial raphe nuclei. In addition, the head-twitch response (HTR) elicited by the intracerebroventricular administration of the 5-HT(2A) agonist 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) was significantly increased in TD versus control mice, whereas the injection of ketanserin, a 5-HT(2A) receptor antagonist, prevented this enhancement. A single injection of thiamine HCl on the 19th day of TD feeding did not reduce the enhanced DOI-induced HTR. On the other hand, the administration of d-fenfluramine, a 5-HT releaser, did not enhance the HTR in TD mice. Together, our results indicate that TD causes a super-sensitivity of 5-HT(2A) receptors by reducing presynaptic 5-HT synthesis derived from degenerating neurons projecting from the raphe nucleus.
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PMID:Enhanced head-twitch response to 5-HT-related agonists in thiamine-deficient mice. 1737 73

Serotonin (5-HT) is involved in many developmental processes and influences behaviors including anxiety, aggression, and cognition. Disruption of the serotonergic system has been implicated in human disorders including autism, depression, schizophrenia, and ADHD. Although pharmacological, neurotoxin, and dietary manipulation of 5-HT and tryptophan hydroxylase has added to our understanding of the serotonergic system, the results are complicated by multiple factors. A newly identified ETS domain transcription factor, Pet-1, has direct control of major aspects of 5-HT neuronal development. Pet-1 is the only known factor that is restricted in the brain to 5-HT neurons during development and adulthood and exerts dominant control over 5-HT neuronal phenotype. Disruption of Pet-1 produces an approximately 80% loss of 5-HT neurons and content and results in increased aggression in male Pet-1(-/-) mice [Hendricks TJ, Fyodorov DV, Wegman LJ, Lelutiu NB, Pehek EA, Yamamoto B, Silver J, Weeber EJ, Sweatt JD, Deneris ES (2003) Neuron 37:233-247]. We hypothesized that Pet-1(-/-) mice would also exhibit changes in anxiety and cognition. Pet-1(-/-) mice were hypoactive which may have affected the observed lack of anxious behavior in the elevated zero maze and light-dark test. Pet-1(-/-) mice, however, were more defensive during marble burying and showed acoustic startle hyper-reactivity. No deficits in spatial, egocentric, or novel object recognition learning were found in Pet-1(-/-) mice. These findings were unexpected given that 5-HT depleting drugs given to adult or developing animals result in learning deficits [Mazer C, Muneyyirci J, Taheny K, Raio N, Borella A, Whitaker-Azmitia P (1997) Brain Res 760:68-73; Morford LL, Inman-Wood SL, Gudelsky GA, Williams MT, Vorhees CV (2002) Eur J Neurosci 16:491-500; Vorhees CV, Schaefer TL, Williams MT (2007) Synapse 61:488-499]. Lack of differences may be the result of compensatory mechanisms in reaction to a constitutive knock out of Pet-1 or 5-HT may not be as important in learning and memory as previously suspected.
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PMID:Mouse plasmacytoma-expressed transcript 1 knock out induced 5-HT disruption results in a lack of cognitive deficits and an anxiety phenotype complicated by hypoactivity and defensiveness. 1978 75

Dysfunction in brain serotonin (5-HT) system has been implicated in the psychopathology of anxiety, depression, drug addiction, and schizophrenia. The 5-HT(1A) receptors play a central role in the control of 5-HTergic neurotransmission. There are some scarce data showing cross-regulation between 5-HT receptors. Here, we investigated whether interaction exists between 5-HT(1A) receptor and genes encoding key members in brain 5-HT system. Chronic treatment with selective agonist of 5-HT(1A) receptor 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (1.0 mg/kg i.p., 14 days) produced considerable decrease in hypothermic response to acute administration of 8-OH-DPAT in CBA/Lac mice indicating desensitization of 5-HT(1A) receptors. The decrease in 5-HT(1A) gene expression as well as decrease in the expression of gene encoding key enzyme in 5-HT synthesis, tryptophan hydroxylase-2 (TPH-2) in the midbrain, and the expression of the gene encoding 5-HT(2A) receptor in the frontal cortex was shown. There were no significant changes in 5-HT transporter mRNA level in the midbrain. Despite considerable decrease in the expression of the genes encoding tryptophan hydroxylase-2, 5-HT(1A) and 5-HT(2A) receptors, chronic 8-OH-DPAT treatment failed to produce significant changes in 5-HT(1A)-linked behavior (intermale aggression, open-field behavior, light-dark box, and pinch-induced catalepsy), suggesting compensatory and adaptive effect of genes suppression. The obtained data on the effect of 8-OH-DPAT-induced desensitization of 5-HT(1A) receptors on 5-HT(1A), 5-HT(2A) and TPH-2 gene expression demonstrated the role of 5-HT(1A) receptor as indirect regulator of gene expression. The results provide the first evidence of receptor-key genes interaction in brain 5-HT system and may have profound implications in understanding the functioning of the brain neurotransmitter systems.
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PMID:Receptor-genes cross-talk: effect of chronic 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino) tetralin treatment on the expression of key genes in brain serotonin system and on behavior. 2042 22

Schizophrenia is a chronic and severe mental illness which is characterized by the development of various detrimental clinical features, and its etiology still remains unknown. Based on the evidence from neurobiological and pharmacological research, dysfunctions in central serotonergic transmission may be involved in the development of schizophrenia. Tryptophan hydroxylase 2 (TPH2), a newly identified isoform of tryptophan hydroxylase (the rate limiting enzyme in the biosynthesis of serotonin), regulates the brain-specific serotonin synthesis. To further clarify the role of TPH2 in this disease, we performed a case-control study to examine the association of the TPH2 gene with schizophrenia and its clinical features. We genotyped three putative functional polymorphisms (rs4570625, rs7305115, and rs4290270) within the gene and carried out a case-control study consisting of 304 schizophrenia patients and 362 healthy subjects. The severity of psychotic symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS). The frequencies of genotypes and alleles of rs4570625, rs7305115, and rs4290270 did not differ significantly between schizophrenic patients and controls. However, the PANSS positive symptom subcore was significantly associated with rs4570625 (P=0.022). These results suggest that rs4570625 of TPH2 may play an important role in the development of positive symptoms in Han Chinese schizophrenic patients.
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PMID:Association study of tryptophan hydroxylase-2 gene in schizophrenia and its clinical features in Chinese Han population. 2093 55

Depression is characterized by sadness, purposelessness, irritability, and impaired body functions. Depression causes severe symptoms for several weeks, and dysthymia, which may cause chronic, low-grade symptoms. Treatment of depression involves psychotherapy, medications, or phototherapy. Clinical and experimental evidence indicates that an appropriate diet can reduce symptoms of depression. The neurotransmitter, serotonin (5-HT), synthesized in the brain, plays an important role in mood alleviation, satiety, and sleep regulation. Although certain fruits and vegetables are rich in 5-HT, it is not easily accessible to the CNS due to blood brain barrier. However the serotonin precursor, tryptophan, can readily pass through the blood brain barrier. Tryptophan is converted to 5-HT by tryptophan hydroxylase and 5-HTP decarboxylase, respectively, in the presence of pyridoxal phosphate, derived from vitamin B(6). Hence diets poor in tryptophan may induce depression as this essential amino acid is not naturally abundant even in protein-rich foods. Tryptophan-rich diet is important in patients susceptible to depression such as certain females during pre and postmenstrual phase, post-traumatic stress disorder, chronic pain, cancer, epilepsy, Parkinson's disease, Alzheimer's disease, schizophrenia, and drug addiction. Carbohydrate-rich diet triggers insulin response to enhance the bioavailability of tryptophan in the CNS which is responsible for increased craving of carbohydrate diets. Although serotonin reuptake inhibitors (SSRIs) are prescribed to obese patients with depressive symptoms, these agents are incapable of precisely regulating the CNS serotonin and may cause life-threatening adverse effects in the presence of monoamine oxidase inhibitors. However, CNS serotonin synthesis can be controlled by proper intake of tryptophan-rich diet. This report highlights the clinical significance of tryptophan-rich diet and vitamin B(6) to boost serotonergic neurotransmission in depression observed in various neurodegenerative diseases. However pharmacological interventions to modulate serotonergic neurotransmission in depression, remains clinically significant. Depression may involve several other molecular mechanisms as discussed briefly in this report.
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PMID:Effect of diet on serotonergic neurotransmission in depression. 2330 10


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