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)

Neurons contain abundant subsets of highly stable microtubules that resist depolymerizing conditions such as exposure to the cold. Stable microtubules are thought to be essential for neuronal development, maintenance, and function. Previous work has indicated an important role of the microtubule-associated protein STOP in the induction of microtubule cold stability. Here, we developed STOP null mice. These mice were devoid of cold-stable microtubules. In contrast to our expectations, STOP-/- mice had no detectable defects in brain anatomy but showed synaptic defects, with depleted synaptic vesicle pools and impaired synaptic plasticity, associated with severe behavioral disorders. A survey of the effects of psychotropic drugs on STOP-/- mice behavior showed a remarkable and specific effect of long-term administration of neuroleptics in alleviating these disorders. This study demonstrates that STOP is a major factor responsible for the intriguing stability properties of neuronal microtubules and is important for synaptic plasticity. Additionally, STOP-/- mice may yield a pertinent model for study of neuroleptics in illnesses such as schizophrenia, currently thought to result from synaptic defects.
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PMID:The suppression of brain cold-stable microtubules in mice induces synaptic defects associated with neuroleptic-sensitive behavioral disorders. 1223 25

Microtubules assembled from purified tubulin in vitro are labile, rapidly disassembling when exposed to a variety of depolymerizing conditions such as cold temperature. In contrast, in many cell types, microtubules seem to be unaffected when the cell is exposed to the cold. This resistance of microtubules to the cold has been intriguing because the earliest and by far most studied microtubule-associated proteins such as MAP2 and tau are devoid of microtubule cold stabilizing activity. Over the past several years, it has been shown that resistance of microtubules to the cold is largely due to polymer association with a class of microtubule-associated proteins called STOPs. STOPs are calmodulin-binding and calmodulin-regulated proteins which, in mammals, are encoded by a single gene but exhibit substantial cell specific variability due to mRNA splicing and alternative promoter use. STOP microtubule stabilizing activity has been ascribed to two classes of new bifunctional calmodulin- and microtubule-binding motifs, with distinct microtubule binding properties in vivo. STOPs seem to be restricted to vertebrates and are composed of a conserved domain split by the apparent insertion of variable sequences that are completely unrelated among species. Recently, STOP suppression in mice has been found to induce synaptic defects associated with neuroleptic-sensitive behavioral disorders. Thus, STOPs are important for synaptic plasticity. Additionally, STOP-deficient mice may yield a pertinent model for the study of neuroleptics in illnesses such as schizophrenia, currently thought to result from defects in synapse function.
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PMID:STOP proteins. 1456 73

Microtubules are key cytoskeletal components in the cytoplasm of eukaryotic cells where they have pleiotropic and vital roles in functions such as cell division, trafficking or morphogenesis. Microtubules are especially abundant in neurons. Although microtubules are in many cells dynamic polymers, they exhibit an extreme state of stability in neurons. Previous work has indicated a central role of microtubule associated proteins called STOPs in neuronal microtubule stabilization. We have recently developed STOP null mice. These mice were devoid of stable brain microtubules but to our surprise had nevertheless an apparently normal brain anatomy. However the mice showed synaptic defects affecting different forms of long- and short-term synaptic plasticity. These synaptic defects were associated with severe behavioral defects that showed a remarkable sensitivity to long-term treatment with neuroleptics. We discuss the relationship of the phenotypes observed in STOP null mice with current models of schizophrenia in which the multiple, severe, and neuroleptic sensitive mental disorders caused by the disease are due to a "disease of the synapse".
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PMID:[A role for microtubules in mental diseases?]. 1500 Dec 37

Neuroleptics are thought to exert their anti-psychotic effects by counteracting a hyper-dopaminergic transmission. Here, we have examined the dopaminergic status of STOP (stable tubule only polypeptide) null mice, which lack a microtubule-stabilizing protein and which display neuroleptic-sensitive behavioural disorders. Dopamine transmission was investigated using both behavioural analysis and measurements of dopamine efflux in different conditions. Compared to wild-type mice in basal conditions or following mild stress, STOP null mice showed a hyper-locomotor activity, which was erased by neuroleptic treatment, and an increased locomotor reactivity to amphetamine. Such a behavioural profile is indicative of an increased dopaminergic transmission. In STOP null mice, the basal dopamine concentrations, measured by quantitative microdialysis, were normal in both the nucleus accumbens and the striatum. When measured by electrochemical techniques, the dopamine efflux evoked by electrical stimulations mimicking physiological stimuli was dramatically increased in the nucleus accumbens of STOP null mice, apparently due to an increased dopamine release, whereas dopaminergic uptake and auto-inhibition mechanisms were normal. In contrast, dopamine effluxes were slightly diminished in the striatum. Together with previous results, the present study indicates the association in STOP null mice of hippocampal hypo-glutamatergy and of limbic hyper-dopaminergy. Such neurotransmission defects are thought to be central to mental diseases such as schizophrenia.
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PMID:Dopaminergic transmission in STOP null mice. 2214 79

Schizophrenia is a chronic and debilitating disease which is thought to arise from a neuro-developmental disorder. Both the stable tubule-only polypeptide (STOP) protein and the N-methyl-D-aspartate (NMDA) NR1 subunit are involved in neuronal development and physiology. It has therefore been postulated that transgenic mice lacking either the STOP or the NMDAR1 gene would show a 'schizophrenic-like' phenotype. Here, STOP knockout and NMDA NR1 hypomorphic mice were assessed in a behavioural measure that can be used to detect schizophrenic-like phenotypes: a change in sensorimotor gating, measured through prepulse inhibition (PPI). STOP knockout mice were further assessed in another measure of 'schizophrenic-like behaviour': hyperlocomotion. The PPI deficit exhibited by both the STOP knockout and NMDA knockdown mice could not be reversed by acute treatment with the atyptical antipsychotic, clozapine (1 mg/kg, i.p.) but the hyperlocomotion shown by the STOP knockout mice was reversed with the same acute dose of clozapine.
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PMID:STOP knockout and NMDA NR1 hypomorphic mice exhibit deficits in sensorimotor gating. 1604 5

Accumulating evidence suggests that the pathologic lesions of schizophrenia may in part be due to the altered cytoskeletal architecture of neurons. Microtubule-associated proteins (MAPs) that bind to cytoskeletal microtubules to stabilize their assembly are prominently expressed in neurons. Of the MAPs, MAP6 (STOP) has a particular relevance to schizophrenia pathology, since mice deficient in the gene display neuroleptic-responsive behavioral defects. Here we examined the genetic contribution of MAP6 to schizophrenia in a case (n = 570) -control (n = 570) study, using dense single nucleotide polymorphism (SNP) markers. We detected nominal allelic (p = 0.0291) and haplotypic (global p = 0.0343 for 2 SNP-window, global p = 0.0138 for 3 SNP-window) associations between the 3' genomic interval of the gene and schizophrenia. MAP6 transcripts are expressed as two isoforms. A postmortem brain expression study showed up-regulation of mRNA isoform 2 in the prefrontal cortex (Brodmann's area 46) of patients with schizophrenia. These data suggest that the contribution of MAP6 to the processes that lead to schizophrenia should be further investigated.
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PMID:Genetic and expression analyses of the STOP (MAP6) gene in schizophrenia. 1662 26

Stable tubule-only polypeptide (STOP) proteins are a family of microtubule associated proteins (MAPs) important in microtubule stabilization. Data indicating a role for microtubules in synaptic function has come from studies of the STOP null mouse, which exhibits synaptic deficits, in association with behavioural changes that are alleviated by antipsychotic treatment. These findings suggested that STOP mutant mice may be useful in studies of synaptic function, and could be especially relevant to schizophrenia, postulated to be a disorder of the synapse. Moreover, a genetic association between STOP and schizophrenia has been reported. This study aimed to further characterize synaptic alterations in STOP null and heterozygous mice. Using in situ hybridization histochemistry, the mRNA expression of three pre-synaptic (synaptophysin; growth associated protein-43 (GAP-43); vesicular glutamate transporter-1 (VGlut1)) and two post-synaptic (spinophilin; MAP2) proteins, was quantified in female STOP null (n = 7), heterozygous (n = 5) and wild type (n = 6) mice. For STOP null and heterozygous mice, synaptophysin, VGlut1, GAP-43 and spinophilin mRNAs were decreased in the hippocampus, whilst in addition in the null mice, synaptophysin, VGlut1 and spinophilin mRNAs were decreased in the cerebellum. Alterations in synaptic protein mRNA expression were also detected in the frontal and occipital cortex. MAP2 mRNA expression was unchanged in all brain regions. The profile of mRNA changes is broadly similar to that observed in schizophrenia. Together the data provide supporting evidence for a role for microtubules in synaptic function, and suggest that STOP, or other microtubule proteins, may contribute to the synaptic pathology of schizophrenia.
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PMID:Altered expression of synaptic protein mRNAs in STOP (MAP6) mutant mice. 1705 Jun 59

Retroviruses-derived elements in the human genome constitute 90% of non-coding mobile sequences. Reverse transcriptase (RT) plays an essential role in their transposition as do long terminal repeats (LTRs), which contain promotors, enhancers, and regulatory sequences. Some retroelements (pseudogens and retrogenes, e.g. SINE) are non-autonomic and do not possess their own RT. These elements are dependent on autonomic elements (retroposons, e.g. LINE, retrotransposons, exo- and endogenous retroviruses). The genome of retroviruses is composed of gag, pol, and env genes flanked by long terminal repeats. Endogenous retroviruses are probably the remnants of ancient germ cell infection by exogenous retroviruses and are transmissible to the next generation in a Mendelian way. Most of them are defective (because of mutation accumulation), but some are still active and their expression is regulated by different factors (UV radiation, inflammatory cytokines, steroid hormones, and exogenous virus products). Retroelements as well as their gene products exert influence on the organism's functions. They influence the plasticity and evolution of genomes, are a source of promotors and regulatory sequences, but they also supply additional signals of transcription initiation, mRNA splicing, and STOP codons. One of the positive aspects of human endogenous retroviruses (HERVs) is the participation of their products in normal syncytiotrophoblast formation. They also block exogenous retrovirus replication by receptor interference or antisense mRNA. Their presence is considered to be connected with a number of autoimmunological diseases (multiple sclerosis, insulin-dependent diabetes mellitus, systemic lupus erythematosus), cancer, or even psychiatric disorders (schizophrenia). There are also other problems connected with the potential role of ERVs in genomic therapy (with retroviruses vectors) and transplantology (xenotransplantation).
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PMID:[Retroviruses-derived sequences in the human genome. Human endogenous retroviruses (HERVs)]. 1719 6

In mice, the deletion of the STOP protein leads to hyperdopaminergia and major behavioral disorders that are alleviated by neuroleptics, representing a potential model of schizophrenia. The reduction of the glutamatergic synaptic vesicle pool in the hippocampus could reflect a disturbance in glutamatergic neurotransmission in this model. Here we examined potential disturbances in energy metabolism and interactions between neurons and glia in 15-week-old STOP KO, wild-type, and heterozygous mice. Animals received [1-(13)C]glucose and [1,2-(13)C]acetate, the preferential substrates of neurons and astrocytes, respectively. Extracts from the whole forebrain and midbrain were analyzed by HPLC, (13)C and (1)H NMR spectroscopy. Amounts and labeling of most metabolites were unchanged. However, glutamine concentration and amount of [4,5-(13)C]glutamine derived from [1,2-(13)C]acetate significantly decreased by 17% and 18%, respectively, in STOP KO compared with wild-type mice. The amount of [4-(13)C]glutamate was decreased in STOP KO and heterozygous compared with wild-type mice. gamma-Aminobutyric acid labeling was not influenced by the genotype. Because STOP-deficient mice have a lower synaptic vesicle density, less glutamate is released to the synaptic cleft, leading to decreased stimulation of the postsynaptic glutamate receptors, reflecting increased glutamine metabolism only in the vicinity of the postsynapse of STOP KO mice.
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PMID:Hypoglutamatergic activity in the STOP knockout mouse: a potential model for chronic untreated schizophrenia. 1730 67

Mice deficient in the microtubule stabilizing protein STOP (stable tubule only polypeptide) show synaptic plasticity anomalies in hippocampus, dopamine hyper-reactivity in the limbic system and severe behavioral deficits. Some of these disturbances are alleviated by long-term antipsychotic treatment. Therefore, this mouse line represents a pertinent model for some aspects of schizophrenia symptomatology. Numerous data support dysfunction of nicotinic neurotransmission in schizophrenia and epidemiological studies show increased tobacco use in schizophrenic patients, in whom nicotine has been reported to improve cognitive deficits and impairment in sensory gating. In this study, we examined potential alterations in cholinergic (ACh) and nicotinic components and functions in STOP mutant mice. STOP KO mice displayed no variation of the density of ACh esterase and beta2* nicotinic receptors (nAChRs), large reductions in the density of vesicular ACh transporter and alpha6* nAChRs and marked increases in the density of alpha7 nAChRs, in some brain areas. STOP KO mice were hypersensitive to the stimulating locomotor effect of nicotine and, interestingly, their impaired performance in learning the cued version of the water maze were improved by administration of the preferential alpha7 nAChR agonist choline. Altogether, our data show that the deletion of the ubiquitous STOP protein elicited restricted alterations in ACh components. They also suggest that nicotinic neurotransmission can be deficient in STOP KO mice and that mutant mice can represent a meaningful model to study some nicotinic dysfunctions and therapeutic treatments.
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PMID:Sustained increase of alpha7 nicotinic receptors and choline-induced improvement of learning deficit in STOP knock-out mice. 1751 60


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