UMLS:C0036341 - FACTA Search

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Query: UMLS:C0036341 (schizophrenia)
60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neurotrophin hypothesis proposes that repetitive neuronal activity enhances the expression, secretion and actions of neurotrophins to modify synaptic transmission and connectivity thereby providing a connection between neuronal activity and synaptic plasticity. Moreover, there is ample evidence that neurotrophins have numerous neuroprotective effects under pathological conditions, which might be important in particular for neurodegenerative diseases such as Alzheimer' disease. Current research postulates that effects during brain development lead to defective neural connectivity and altered biochemical functioning resulting in cognitive, emotional and intentional dysfunction later in life. This implicates a possible role in most psychiatric diseases including affective and schizophrenic disorders. This hypothesis is mainly based on new experimental evidence showing that psychiatric disorders are associated with neuronal atrophy and cell loss, impairments of structural plasticity and cellular resilience due to neurodevelopmental disturbances and morphological abnormalities of the brain. Thus, the potential role of neurotrophins in psychiatric disorders has been studied in different ways. Animal studies indicate the involvement of neurotrophins in psychopharmacological therapies and they show that gene expression of cerebral neurotrophins is changed in animal models of several psychiatric disorders. Whether such alterations are causatively associated with increased neural plasticity, improved cognitive function and decreased depressive mood states remains to be elucidated in further studies including man (e.g. in postmortem studies of patients). Association studies tried to link different variants in genes coding for neurotrophins, they have not been conclusive however. They partially allow to separate different subgroups of patients with differing therapy response profiles or indicate an increased vulnerability for a specific disorder. Finally, neurotrophin serum changes have been observed in most psychiatric disorders. The question remains though whether these alterations represent primary-causal or secondary-reactive changes.In conclusion, the issue of neuroprotection and neurotrophins is recognised as an important new lead in the quest for a deeper understanding of psychiatric disorders and the mechanisms of action of psychopharmacological interventions.
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PMID:State of the art of the neurotrophin hypothesis in psychiatric disorders: implications and limitations. 1499 61

Infection of the central nervous system by Borna disease virus (BDV) provides a unique model to study the mechanisms whereby a persistent viral infection can impair neuronal function and cause behavioral diseases reminiscent of mood disorders, schizophrenia, or autism in humans. In the present work, we studied the effect of BDV infection on the response of hippocampal neurons, the main target for this virus, to the neurotrophin BDNF. We showed that persistent infection did not affect neuronal survival or morphology. However, it blocked BDNF-induced ERK 1/2 phosphorylation, despite normal expression of the TrkB BDNF receptor. In addition, BDNF-induced expression of synaptic vesicle proteins was abrogated, which resulted in severely impaired synaptogenesis and defects in synaptic organization. Thus, we provide the first evidence that a virus can interfere specifically with neurotrophin-regulated neuroplasticity, thereby hampering proper neuronal connectivity. These results may help to understand the behavioral disorders associated with BDV infection.
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PMID:Persistent, noncytolytic infection of neurons by Borna disease virus interferes with ERK 1/2 signaling and abrogates BDNF-induced synaptogenesis. 1503 26

Glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors mediate most of the excitatory neurotransmission in the mammalian central nervous system and also participate in forms of synaptic plasticity thought to underlie memory and learning, and the formation of neural networks during development. Molecular cloning techniques have shown that the AMPA receptor family is composed of four different subunits named GluR1-4 or GluRA-D (newly termed as Glu(A1)-Glu(A4)) and native AMPA receptors are most likely tetramers generated by the assembly of one or more of these subunits, yielding homomeric or heteromeric receptors. Additional complexity among AMPA receptors is conferred by alternative splicing of RNA for each subunit giving rise to flip and flop variants. Clinical and experimental data have suggested that positive modulation of AMPA receptors may be therapeutically effective in the treatment of cognitive deficits. Several classes of AMPA receptor potentiators have been reported, including pyrroliddones (piracetam, aniracetam), benzothiazides (cyclothiazide), benzylpiperidines (CX-516, CX-546) and more recently biarylpropylsulfonamides (LY392098, LY404187 and LY503430). These molecules enhance cognitive function in rodents, which appears to correlate with increased hippocampal activity. In addition, clinical studies have suggested that AMPA receptor modulators enhance cognitive function in elderly subjects, as well as patients suffering from neurological and psychiatric disorders. Several independent studies have suggested that AMPA receptors can increase BDNF expression by both calcium-dependent and independent pathways. For example, recent studies have shown that AMPA receptors interact with the protein tyrosine kinase, Lyn. Activation of Lyn can recruit the mitogen-activated protein kinase (MAPK) signalling pathway and increase the expression of BDNF. Therefore, in addition to directly enhancing glutamatergic synaptic transmission, AMPA receptor activation can increase the expression of BDNF in vitro and in vivo. This may account for activity of AMPA receptor potentiators in rodent models predictive of antidepressant activity (forced swim and tail suspension tests). The increase in neurotrophin expression also may contribute to the functional, neuroprotective and neurotrophic actions of LY404187 and LY503430 after infusion of 6-OHDA into the substantia nigra. In conclusion, several potent, selective and systemically active AMPA receptor potentiators have been reported. Data indicate that these molecules modulate glutamatergic transmission, enhance synaptic transmission, long-term potentiation (LTP) and increase neurotrophin expression. Therefore, these AMPA receptor potentiators offer an exciting new class of drugs with potential for treating (1) cognitive impairment associated with Alzheimer's disease and schizophrenia, (2) depression, (3) slowing the progression and potentially enhancing recovery from Parkinson's disease.
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PMID:AMPA receptor potentiators for the treatment of CNS disorders. 1518 Apr 79

Several neuropsychiatric disorders, including schizophrenia, are the consequence of a disrupted development of the CNS. Accordingly, intrauterine exposure to toxins may increase the risk for psychopathology. We investigated whether prenatal exposure of rats to the neurotoxin methylazoxymethanol acetate led to long-term changes in cerebral neurotrophin levels. We measured the brain levels of nerve growth factor and brain derived neurotrophic factor in young adult and adult rats. Decreased nerve growth factor or brain derived neurotrophic factor were found in the parietal cortex accompanied by altered neurotrophin content in the hippocampus and entorhinal cortex. The present study is the first to show long-lasting effects of a single prenatal exposure to a neurotoxin on adult levels of neurotrophins in brain regions implicated in neuropsychiatric disorders.
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PMID:Impaired brain development in the rat following prenatal exposure to methylazoxymethanol acetate at gestational day 17 and neurotrophin distribution. 1525 49

Prenatal stress represents a well-established experimental protocol resembling some features of schizophrenia, including deficits in social interactions, disruption of prepulse inhibition and enhanced response to psychomotor stimulants. In order to evaluate molecular changes that could participate in long-lasting effects on brain function, we analysed the effects of prenatal stress on the expression of brain-derived neurotrophic factor (BDNF), an important molecular determinant of synaptic plasticity and cellular homeostasis, in adult male rats under basal conditions as well as in response to a chronic stress. The main finding is that BDNF expression is reduced in the prefrontal cortex and striatum of prenatally stressed rats. Furthermore, when exposed to chronic stress in adulthood, these rats display an altered regulation of BDNF expression in these brain structures, implying that adverse life events during gestation may interfere with the expression and function of this neurotrophin at adulthood in a region-specific manner. The dysregulation of corticostriatal BDNF expression might thus contribute to permanent alterations in brain functions leading to heightened susceptibility to psychiatric disorders.
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PMID:Corticostriatal brain-derived neurotrophic factor dysregulation in adult rats following prenatal stress. 1534 6

A decrease in the number of nicotinic-acetylcholine receptors (nAChRs) in the brain is thought to contribute to the cognitive dysfunction associated with diseases as diverse as Alzheimer's disease and schizophrenia. Interestingly, nicotine and similar compounds have been shown to enhance memory function and increase the expression of nAChRs and therefore, could have a therapeutic role in the aforementioned diseases. Nicotine has also been shown to exert positive effects on certain neurotrophins such as nerve growth factor (NGF), and therefore could play a role beyond mere symptomatic therapy. However, to date, comprehensive studies of nicotine's effects on the expression of specific acetylcholine (ACh) receptor subtypes, key cholinergic proteins (that are regulated by NGF) such as choline acetyltransferase (ChAT) and the vesicular ACh transporter (VAChT) are lacking. Studies to further investigate the effects of nicotine on NGF especially its high- and low-affinity receptors are also needed. In the present study, male Wistar rats exposed a relatively low dosage of nicotine (0.35 mg/kg every 12 h) for 14 days demonstrated improved memory performance (assessed in two separate water maze testing methods) when compared with controls. Autoradiographic experiments indicated that nicotine increased [3H]-epibatidine, [125I]-alpha-bungarotoxin and [3H]-AFDX384, but not [3H]-pirenzepine binding sites in several learning- and memory-related brain areas. The expression of ChAT, VAChT, as well as tropomyosin-receptor kinase A (TrkA) NGF receptors and phospho-TrK receptors was increased by nicotine in the hippocampus. No changes were observed in the levels of the NGF peptide or low affinity p75 neurotrophin receptors (p75NTR), however. These results suggest that repeated exposure to nicotine results in positive effects on central cholinergic markers and memory function, which may be mediated via effects on high-affinity NGF receptors.
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PMID:Repeated nicotine exposure in rats: effects on memory function, cholinergic markers and nerve growth factor. 1565 96

The S100B gene locates in 21q22.3 and produces neurotrophin mainly in astrocytes of CNS which can act as an extensive marker of glial cell integrity. The synaptic destabilization hypothesis (GGF/SD) suggests that the functional deficiency of growth factors like S100B is involved in the etiology of schizophrenia and the S100B serum concentration is reported to be significantly increased in patients with acute schizophrenia and decreased in chronic schizophrenia patients. To validate the association between S100B and schizophrenia, 384 cases and 401 controls, all Chinese Han subjects, were recruited. Four SNPs V1 (-960C>G), V2 (-111C>T), V3 (2757C>G, rs1051169), and V4 (5748C>T, rs9722) were studied. And haplotype V3-V4 (G-C) showed a significant association with schizophrenia. Our study showed an association between schizophrenia and a possible susceptible haplotype V3-V4 (G-C) which possesses a genetic tendency for increased S100B expression. Our results suggest that S100B could be a susceptible gene for schizophrenia and provide indirect evidence for the GGF/SD hypothesis.
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PMID:SNPs and haplotypes in the S100B gene reveal association with schizophrenia. 1567 Jul 88

Impairments in certain cognitive functions, such as working memory, are core features of schizophrenia. Convergent findings indicate that a deficiency in signalling through the TrkB neurotrophin receptor leads to reduced GABA (gamma-aminobutyric acid) synthesis in the parvalbumin-containing subpopulation of inhibitory GABA neurons in the dorsolateral prefrontal cortex of individuals with schizophrenia. Despite both pre- and postsynaptic compensatory responses, the resulting alteration in perisomatic inhibition of pyramidal neurons contributes to a diminished capacity for the gamma-frequency synchronized neuronal activity that is required for working memory function. These findings reveal specific targets for therapeutic interventions to improve cognitive function in individuals with schizophrenia.
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PMID:Cortical inhibitory neurons and schizophrenia. 1580 62

Based on clues from epidemiology, low prenatal vitamin D has been proposed as a candidate risk factor for schizophrenia. Recent animal experiments have demonstrated that transient prenatal vitamin D deficiency is associated with persistent alterations in brain morphology and neurotrophin expression. In order to explore the utility of the vitamin D animal model of schizophrenia, we examined different types of learning and memory in adult rats exposed to transient prenatal vitamin D deficiency. Compared to control animals, the prenatally deplete animals had a significant impairment of latent inhibition, a feature often associated with schizophrenia. In addition, the deplete group was (a) significantly impaired on hole board habituation and (b) significantly better at maintaining previously learnt rules of brightness discrimination in a Y-chamber. In contrast, the prenatally deplete animals showed no impairment on the spatial learning task in the radial maze, nor on two-way active avoidance learning in the shuttle-box. The results indicate that transient prenatal vitamin D depletion in the rat is associated with subtle and discrete alterations in learning and memory. The behavioural phenotype associated with this animal model may provide insights into the neurobiological correlates of the cognitive impairments of schizophrenia.
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PMID:Transient prenatal vitamin D deficiency is associated with subtle alterations in learning and memory functions in adult rats. 1592 58

Patients with schizophrenia have reduced neurotrophin levels in their dorsolateral prefrontal cortex (DLPFC) compared to normal unaffected individuals. The tyrosine kinase-containing receptors, trkB and trkC, mediate the growth-promoting effects of neurotrophins and respond to changes in growth factor availability. We hypothesized that trkB and/or trkC expression would be altered in the DLPFC of patients with schizophrenia. We measured mRNA encoding the tyrosine kinase domain (TK+)-containing form of trkB and measured pan trkC mRNA in schizophrenics (N=14) and controls (N=15) using in situ hybridization. TrkB and trkC mRNAs were detected in large and small neurons in multiple cortical layers of the human DLPFC. We found significantly diminished expression of trkB(TK+) mRNA in large neurons in multiple cortical layers of patients as compared to controls, while small neurons also showed reductions in trkB(TK+) mRNA that did not reach statistical significance. In normals, strong positive correlations were found between trkB(TK+) mRNA levels and brain-derived neurotrophic factor (BDNF) mRNA levels among various neurons, while no correlation between BDNF and trkB(TK+) was found in patients with schizophrenia. TrkC mRNA was also reduced in the DLPFC of schizophrenics in large neurons in layers II, III, V and VI and in small neurons in layer IV. Since neurons in the DLPFC integrate and communicate signals to various cortical and subcortical regions, these reductions in growth factor receptors may compromise the function and plasticity of the DLPFC in schizophrenia.
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PMID:Reductions in neurotrophin receptor mRNAs in the prefrontal cortex of patients with schizophrenia. 1594 Mar 4

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