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)

The thalamus relays information to the cerebral cortex from subcortical centers or other cortices; in addition, it projects to the striatum and amygdala. The thalamic relay function is subject to modulation, so the flow of information to the target regions may change depending on behavioral demands. Modulation of thalamic relay by dopamine is not currently acknowledged, perhaps because dopamine innervation is reportedly scant in the rodent thalamus. We show that dopaminergic axons profusely target the human and macaque monkey thalamus using immunolabeling with three markers of the dopaminergic phenotype (tyrosine hydroxylase, dopamine, and the dopamine transporter). The dopamine innervation is especially prominent in specific association, limbic, and motor thalamic nuclei, where the densities of dopaminergic axons are as high as or higher than in the cortical area with the densest dopamine innervation. We also identified the dopaminergic neurons projecting to the macaque thalamus using retrograde tract-tracing combined with immunohistochemistry. The origin of thalamic dopamine is multiple, and thus more complex, than in any other dopaminergic system defined to date: dopaminergic neurons of the hypothalamus, periaqueductal gray matter, ventral mesencephalon, and the lateral parabrachial nucleus project bilaterally to the monkey thalamus. We propose a novel dopaminergic system that targets the primate thalamus and is independent from the previously defined nigrostriatal, mesocortical, and mesolimbic dopaminergic systems. Investigating this "thalamic dopaminergic system" should further our understanding of higher brain functions and conditions such as Parkinson's disease, schizophrenia, and drug addiction.
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PMID:The primate thalamus is a key target for brain dopamine. 1598 37

We previously identified frequent deletion/insertion polymorphisms in the 20-alanine homopolymer stretch of PHOX2B (PMX2B), the gene for a transcription factor that plays important roles in the development of oculomotor nerves and catecholaminergic neurons and regulates the expression of both tyrosine hydroxylase and dopamine beta-hydroxylase genes. An association was detected between gene polymorphisms and overall schizophrenia, and more specifically, schizophrenia with ocular misalignment. These prior results implied the existence of other schizophrenia susceptibility genes that interact with PHOX2B to increase risk of the combined phenotype. ASCL1 was considered as a candidate interacting partner of PHOX2B, as ASCL1 is a transcription factor that co-regulates catecholamine-synthesizing enzymes with PHOX2B. The genetic contributions of PHOX2B and ASCL1 were examined separately, along with epistatic interactions with broader candidate phenotypes. These phenotypes included not only schizophrenia, but also bipolar affective disorder and Parkinson's disease (PD), each of which involve catecholaminergic function. The current case-control analyses detected nominal associations between polyglutamine length variations in ASCL1 and PD (P=0.018), but supported neither the previously observed weak association between PHOX2B and general schizophrenia, nor other gene-disease correlations. Logistic regression analysis revealed the effect of ASCL1 dominant x PHOX2B additive (P=0.008) as an epistatic gene-gene interaction increasing risk of PD. ASCL1 controls development of the locus coeruleus (LC), and accumulating evidence suggests that the LC confers protective effects against the dopaminergic neurodegeneration inherent in PD. The present genetic data may thus suggest that polyglutamine length polymorphisms in ASCL1 could influence predispositions to PD through the fine-tuning of LC integrity.
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PMID:Genetic association analyses of PHOX2B and ASCL1 in neuropsychiatric disorders: evidence for association of ASCL1 with Parkinson's disease. 1602 68

Neurokinin-1 receptors show activity-dependent changes in their surface distributions that are critical in spinal pain mechanisms, and also may play an important role in the motor and affective behaviors influenced by dopaminergic projections from the substantia nigra and ventral tegmental area. To determine the relevant sites for neurokinin-1 receptor activation in these midbrain regions, we examined the electron microscopic immunolabeling of neurokinin-1 receptors and the dopamine-synthesizing enzyme, tyrosine hydroxylase in normal rats. We also examined whether neurokinin-1 receptor distributions in one or both regions are affected by (1) startle-evoking intense auditory stimulation or (2) acute administration of apomorphine, a dopamine D1/D2 agonist that enhances startle while paradoxically reducing the prepulse inhibition produced by low intensity conditioning stimuli in rat models of schizophrenia. In each region, neurokinin-1 immunogold was located on the plasma membrane and endomembranes of somatodendritic profiles with or without tyrosine hydroxylase. As compared with controls, animals receiving intense auditory stimulation either alone or together with smaller low intensity prepulses showed a significant increase in neurokinin-1-plasmalemmal labeling in non-dopaminergic dendrites of both regions, and a reduction in this labeling in dopaminergic dendrites of the ventral tegmental area. Both effects were diminished following apomorphine administration. In absence of the intense auditory stimulation, however, apomorphine increased neurokinin-1-immunogold particles on the plasma membrane of the non-dopaminergic dendrites exclusively in the substantia nigra. Our results are the first to show that neurokinin-1 receptors have plasmalemmal distributions in dopaminergic and non-dopaminergic neurons that can be differentially modified by startle-evoking auditory stimulation. They suggest that while apomorphine can independently affect neurokinin-1 receptor trafficking in substantia nigra motor circuits, its effects on neurokinin-1 receptor distributions in the ventral tegmental area are exclusively dependent on sensory activation.
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PMID:Subcellular distribution and plasticity of neurokinin-1 receptors in the rat substantia nigra and ventral tegmental area. 1616 96

A previous study on the human tyrosine hydroxylase (TH) promoter revealed remarkable differences in the mechanism of TH gene regulation between the human and murine models. Indeed, a low degree of homology was observed in the sequence of TH promoters among human, mouse, and rat systems. Only five short conserved regions (CRs) could be identified among the three species. A human TH minimal promoter was engineered and assembled into a self-inactivating lentiviral vector system. This human TH minimal promoter contained the five CRs plus the first -194 bp from the transcription start of the human TH promoter and the first 35 bp of the untranslated messenger RNA leader of the human TH gene. A significant degree of specificity for this human TH minimal promoter was observed only for human neuronal progenitor cells (hNPCs), but not for TH-positive differentiated mouse primary striatal and substantia nigra cells, indicating a significant difference in TH gene regulation between the human and mouse systems. Not only is the degree of homology between the human and mouse promoters in the range of only 46%, but also those few elements that share a high degree of homology display totally different functions in human and mouse brain-derived cells. In the rodent system, NR4A2 (Nurr1) is required for the transactivation of TH minimal promoters. Intriguingly, neither the dimeric nor the heterodimeric binding sites for Nurr1 are present in the 13 kb DNA sequence that contains the human TH promoter. Instead, the CRs termed one and four of the human TH promoter encode only for a half palindromic binding site sequence for Nurr1, which failed to bind Nurr1 in an in vitro electrophoretic mobility shift assay (EMSA). Additionally, of the three monomeric NGFI-B response element (NBRE) core sites (AGGTCA) and two NBRE-related sites present in the human TH promoter, only one core and two NBRE-related sites formed protein binding complexes. Interestingly, there was no increase of protein binding complex formation upon TH induction and in no case could antibodies supershift Nurr1 from the complex. These findings, taken together, demonstrate that NBRE-related binding sites for Nurr1 do not play a direct role in mediating an interaction between Nurr1 and the human TH promoter. Likewise, immunohistochemical and Western blot analysis have also confirmed that both endogenous and exogenous Nurr1 expression does not positively correlate with TH gene expression in hNPCs, in contrast to the mouse model. In addition, real-time PCR analysis revealed that the downregulation of human Nurr1 gene expression mediated by silencing RNA molecules did not affect human TH gene expression in differentiated hNPCs. A better understanding of human TH gene regulation may have important implications both for the development of novel therapeutic approaches and the study of the pathogenesis of a variety of neurological illnesses, including Parkinson's disease, bipolar disorder, and schizophrenia.
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PMID:Tyrosine hydroxylase gene regulation in human neuronal progenitor cells does not depend on Nurr1 as in the murine and rat systems. 1625 82

Voluntary movement in animals is modulated by a number of subcortical systems. One of these resides in the basal nuclei and their associated projections and utilizes dopamine as a neurotransmitter. Apart from regulating movement, the dopaminergic axis is also involved in the control of goal-oriented behavior, cognition, and mood. Disorders of this system result in common human neurologic disorders such as Parkinson's and Huntington's diseases, as well contributing to a host of behavioral conditions, such as schizophrenia, attention deficit hyperactivity disorder, and addiction. Many individual mouse models of human dopaminergic dysfunction have been described in varying degrees of detail. However, when evaluating this region of the brain, the veterinary pathologist is confronted by a paucity of information summarizing the comparative aspects of the anatomy, physiology, and pathology of the central dopaminergic system. In this review, a systematic approach to anatomic phenotyping of the central dopaminergic system in the mouse is described and illustrated using tyrosine hydroxylase immunohistochemistry. Differences between murine neuroanatomy and comparable regions of the nonhuman primate brain are highlighted. Although the mouse is the focus of this review, conditions in domestic animals characterized by lesions within the basal nuclei and its projections are also briefly described. Murine behavioral and motor tests that accompany abnormalities of specific anatomic regions of the dopaminergic axis are summarized. Finally, we review mouse models of Parkinson's and Huntington's diseases, as well as those genetically altered mice that elucidate aspects of dopamine metabolism and receptor function.
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PMID:Neuroanatomical phenotyping in the mouse: the dopaminergic system. 1630 71

Frontal cortical efferent fibers are thought to have important regulatory influence on cortico-basal ganglia (BG) circuits. The cortico-midbrain (substantia nigra/ventral tegmental area, SN/VTA) pathway has received particular attention in psychiatric diseases, most notably schizophrenia. Work in rodents demonstrates that the prefrontal cortico (PFC)-midbrain pathway plays a central role in regulating the firing pattern of dopamine (DA) neurons. These findings have led to some important hypotheses concerning PFC/BG interaction in schizophrenia. Descending PFC projections to the SN/VTA have been primarily documented in the rodent. The aim of this study was to determine the degree and organization of PFC afferents to these areas in the Macaque monkey. Anterograde tracer injections were made into discrete orbital, cingulate, and dorsolateral prefrontal areas. Projections were charted to the SN and VTA. Overall, there were very few fibers in the ventral midbrain following injections confined to specific areas of the PFC. To determine the relationship of the descending fibers to the midbrain DA neurons, sections were double stained for the tracer molecules and for tyrosine hydroxylase. In all cases, the prefrontal projections and the TH-positive cells did not appear to be in close juxtaposition. The results show a very limited projection from the PFC to the midbrain DA neurons in primates, terminating both within the SN proper as well as in the VTA. They arise from a broad region of the PFC, including the DLPF, cingulate, and orbital cortices. However, despite the relative lack of cortical input to the midbrain cells, these neurons are rich in glutamate receptors in primates. Thus, while, based on these anatomical studies, direct cortical control of DA neurons remains debatable in primates; the cortex may directly impact other sources of glutamatergic control.
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PMID:Prefrontal cortical projections to the midbrain in primates: evidence for a sparse connection. 1639 9

Dysfunction in water intake and metabolism has frequently been reported in schizophrenia. The general population of schizophrenics under neuroleptic treatment secretes lower amounts of vasopressin than controls at comparable values of plasma osmolality. The purpose of the present study was to investigate the synthetic activity of vasopressin neurons of the dorsolateral supraoptic nucleus in schizophrenia on postmortem material using a battery of histochemical activity markers. Our material consisted of formalin-fixed and paraffin-embedded hypothalami from 5 schizophrenic patients under neuroleptic treatment and from 5 matched controls, obtained from The Netherlands' Brain Bank. DSM-III or DSM-IV criteria were used for the clinical diagnosis. The histochemical markers used to study the neuronal activity of the magnocellular vasopressin-synthesizing neurons were: cell size, size of the Golgi apparatus, and expression of vasopressin and tyrosine hydroxylase mRNA by in situ hybridization. Morphometric evaluation and statistical analysis (Mann-Whitney U test) were performed. Our results showed no statistically significant differences in any of the neuronal activity markers between schizophrenic patients and controls. Therefore, the neurosecretory activity of vasopressin neurons of the dorsolateral part of the supraoptic nucleus does not appear to be changed in schizophrenic patients under medication. Since our sample did not include patients with reported polydipsia or hyponatremia, prospective investigation is needed to evaluate the above-mentioned neuronal activity markers in such a particular subgroup of schizophrenic patients.
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PMID:Absence of a difference in the neurosecretory activity of supraoptic nucleus vasopressin neurons of neuroleptic-treated schizophrenic patients. 1641 96

The relatively high comorbidity of type 2 diabetes and schizophrenia may suggest a shared biological susceptibility to these two conditions. Family studies have demonstrated an increased risk of diabetes in unaffected relatives of patients with schizophrenia, consistent with a heritable susceptibility trait. Linkage analyses have identified several loci that are associated with schizophrenia and some of these, notably those on chromosomes 2p22.1-p13.2 and 6g21-824.1 have also been observed in linkage studies in type 2 diabetes. In addition, the dopamine D5 receptor on chromosome 5 and the tyrosine hydroxylase gene on chromosome 11 have both been suggested as candidate genes in schizophrenia and may also be implicated in susceptibility to poor glycaemic control. In addition, an increased rate of type II diabetes has been observed in some patients treated with antipsychotics. Potential neurochemical substrates of this effect include the histamine H1 receptor, the 5-HT2C serotonin receptor or the beta3 adrenoreceptor. However, the search for a genetic basis to the association between diabetes and schizophrenia is still in its infancy, and much further work needs to be performed, including the systematic screening of all confirmed susceptibility loci and quantitative trait locus mapping of glycaemic control.
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PMID:Schizophrenia, antipsychotics and diabetes: Genetic aspects. 1645 47

Developing and mature midbrain dopamine (DA) neurons express fibroblast growth factor (FGF) receptor-1 (FGFR1). To determine the role of FGFR1 signaling in the development of DA neurons, we generated transgenic mice expressing a dominant negative mutant [FGFR1(TK-)] from the catecholaminergic, neuron-specific tyrosine hydroxylase (TH) gene promoter. In homozygous th(tk-)/th(tk-) mice, significant reductions in the size of TH-immunoreactive neurons were found in the substantia nigra compacta (SNc) and the ventral tegmental area (VTA) at postnatal days 0 and 360. Newborn th(tk-)/th(tk-) mice had a reduced density of DA neurons in both SNc and VTA, and the changes in SNc were maintained into adulthood. The reduced density of DA transporter in the striatum further demonstrated an impaired development of the nigro-striatal DA system. Paradoxically, the th(tk-)/th(tk-) mice had increased levels of DA, homovanilic acid and 3-methoxytyramine in the striatum, indicative of excessive DA transmission. These structural and biochemical changes in DA neurons are similar to those reported in human patients with schizophrenia and, furthermore, these th(tk-)/th(tk-) mice displayed an impaired prepulse inhibition that was reversed by a DA receptor antagonist. Thus, this study establishes a new developmental model for a schizophrenia-like disorder in which the inhibition of FGF signaling leads to alterations in DA neurons and DA-mediated behavior.
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PMID:Fibroblast growth factor receptor signaling affects development and function of dopamine neurons - inhibition results in a schizophrenia-like syndrome in transgenic mice. 1652 69

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


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