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)

Recognizing the value of including complex pyridines in small-molecule screening collections, we developed a previously unexplored [2 + 2 + 2]-cycloaddition of silyl-tethered diynes with nitriles. The tether provides high regioselectivity, while the solvent THF allows catalytic CpCo(CO)(2) to be used without exogenous irradiation. One of the resulting bicyclic and monocyclic (desilylated) pyridines was identified as an inhibitor of neuregulin-induced neurite outgrowth (EC(50) = 0.30 microM) in a screen that probes a pathway likely to be involved in breast cancers and schizophrenia.
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PMID:Diversity synthesis of complex pyridines yields a probe of a neurotrophic signaling pathway. 1851 Mar 33

The familial-genetic relationship between affective and schizophrenic disorders is receiving a re-emergence of interest. The reasons are a series of cross-diagnostic molecular-genetic discoveries: specific alleles in the genes for dysbindin (DTNBP1), neuregulin (NRG1) and DAOA (G72/G30) reveal associations for each of both groups of disorders in the same direction in some but not all reported studies. These findings cannot just be false positives because of confirming metaanalyses. Furthermore there is some pathophysiological support: the mentioned genes are involved in biochemical pathways, which are contributing to both disorders partly in a similar and partly in a different manner. The new levels of evidence enrich the classical continuity/discontinuity debate on the relationship between both groups of disorders.
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PMID:Common risk genes for affective and schizophrenic psychoses. 1851 16

Neuregulin-1 (Nrg1)/erbB signaling regulates neuronal development, migration, myelination, and synaptic maintenance. The Nrg1 gene is a schizophrenia susceptibility gene. To understand the contribution of Nrg1 signaling to adult brain structure and behaviors, we studied the regulation of type III Nrg1 expression and evaluated the effect of decreased expression of the type III Nrg1 isoforms. Type III Nrg1 is transcribed by a promoter distinct from those for other Nrg1 isoforms and, in the adult brain, is expressed in the medial prefrontal cortex, ventral hippocampus, and ventral subiculum, regions involved in the regulation of sensorimotor gating and short-term memory. Adult heterozygous mutant mice with a targeted disruption for type III Nrg1 (Nrg1(tm1.1Lwr+/-)) have enlarged lateral ventricles and decreased dendritic spine density on subicular pyramidal neurons. Magnetic resonance imaging of type III Nrg1 heterozygous mice revealed hypofunction in the medial prefrontal cortex and the hippocampal CA1 and subiculum regions. Type III Nrg1 heterozygous mice also have impaired performance on delayed alternation memory tasks, and deficits in prepulse inhibition (PPI). Chronic nicotine treatment eliminated differences in PPI between type III Nrg1 heterozygous mice and their wild-type littermates. Our findings demonstrate a role of type III Nrg1 signaling in the maintenance of corticostriatal components and in the neural circuits involved in sensorimotor gating and short-term memory.
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PMID:Type III neuregulin-1 is required for normal sensorimotor gating, memory-related behaviors, and corticostriatal circuit components. 1859 62

During adolescence there is a loss of approximately 30% of the synapses formed in the cortex during childhood. Comprehensive studies of the visual cortex show that this loss of synapses does not occur as a consequence of less appropriate projections being eliminated in favour of more appropriate ones. Rather it seems that synapses with low efficacy for transmission are eliminated in favour of those with higher efficacy. The loss of low-efficacy synapses is known, on theoretical grounds, to enhance the function of neural networks, but large synapse losses lead to failure of network function. In the dorsolateral prefrontal cortex (DLPC) of those suffering from schizophrenia the number of synapses is relatively very low, approximately 60% lower than that observed in normal childhood. It is not known if this is due to an additional loss over that during normal adolescence or whether it results from a failure to form a normal complement of synapses during childhood. The first study of synapse loss in the mammalian nervous system was made on the neuromuscular junction at Sydney University in 1974. Since then this junction has provided principal insights into the molecular basis of synapse formation and regression, so providing a paradigm for investigations of these phenomena in the DLPC. For example the molecules muscle-specific receptor tyrosine kinase (MuSK), agrin and neuregulin have been identified and their critical roles in the formation and maintenance of synapses elucidated. Loss of function of MuSK or agrin leads to failure of neuromuscular synapse formation as well as a loss of approximately 30% of excitatory synapses in the cortex. Similar synapse loss occurs on failure of neuregulin in vitro and of neuroligin in vivo. It is suggested that three important questions need to be answered: first, over what development period are the synapse numbers in DLPC of subjects with schizophrenia lower than normal; second, what are the relative importance of MuSK/agrin, neuregulin/ErB and neurexin/neuroligin in synapse formation and regression in the DLPC; and third, to what extent have these molecules gone awry in schizophrenia.
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PMID:Dual constraints on synapse formation and regression in schizophrenia: neuregulin, neuroligin, dysbindin, DISC1, MuSK and agrin. 1929 96

Alterations in gamma-frequency oscillations are implicated in psychiatric disorders, and polymorphisms in NRG-1 and ERBB4, genes encoding Neuregulin-1 (NRG-1) and one of its receptors, designated ErbB4, are associated with schizophrenia. Here we show that NRG-1 selectively increases the power of kainate-induced, but not carbachol-induced, gamma oscillations in acute hippocampal slices. NRG-1beta is more effective than NRG-1alpha, a splice variant with lower affinity for ErbB receptors, and neither isoform affects the network activity without prior induction of gamma oscillations. NRG-1beta dramatically increases gamma oscillation power in hippocampal slices from both rats (2062 +/- 496%) and mice (710 +/- 299%). These effects of NRG-1beta are blocked by PD158780, a pan-specific antagonist of ErbB receptors, and are mediated specifically via ErbB4 receptors, because mice harboring a targeted mutation of ErbB4 do not respond to NRG-1. Moreover, we demonstrate that 50% of gamma-amino butyric acidergic parvalbumin (PV)-positive interneurons, which heavily contribute to the generation of gamma oscillations, express ErbB4 receptors. Importantly, both the number of PV-immunoreactive interneurons (-31%) and the power of kainate-induced gamma oscillations (-60%) are reduced in ErbB4 knockout mice. This study provides the first plausible link between NRG-1/ErbB4 signaling and rhythmic network activity that may be altered in persons with schizophrenia.
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PMID:Neuregulin-1 modulates hippocampal gamma oscillations: implications for schizophrenia. 1863 42

Catechol-O-methyltransferase is an important enzyme in the metabolism of dopamine and an important regulator of aspects of dopamine-dependent working memory in prefrontal cortex that are disturbed in schizophrenia. This study investigated the phenotype of mice with heterozygous deletion vs. homozygous knockout of the catechol-O-methyltransferase gene across paradigms that access processes relevant for psychotic illness. Homozygotes evidenced improved performance in spontaneous alternation, an index of immediate spatial working memory; this effect appeared more substantive in males and was reflected in performance in aspects of the Barnes maze, an index of spatial learning/memory. Heterozygotes evidenced impaired performance in object recognition, an index of recognition memory; this effect was evident for both sexes at a retention interval of 5 min but appeared more enduring in males. There were no material effects for either genotype in relation to sociability or social novelty preference. While homozygous catechol-O-methyltransferase deletion results in improvement in spatial learning/working memory with little effect on social behavior, heterozygous deletion results in impairment of recognition memory. We have reported recently, using similar methods, that mice with deletion of the schizophrenia risk gene neuregulin-1 evidence disruption to social behavior, with little effect on spatial learning/working memory. The data suggest that catechol-O-methyltransferase and neuregulin-1 may influence, respectively, primarily cognitive and social endophenotypes of the overall schizophrenia syndrome.
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PMID:Phenotypic characterization of cognition and social behavior in mice with heterozygous versus homozygous deletion of catechol-O-methyltransferase. 1867 97

Schizophrenia is a debilitating lifelong disorder affecting up to 1% of the population worldwide, producing significant financial and emotional hardship for patients and their families. As yet, the causes of schizophrenia and the mechanism of action of antipsychotic drugs are unknown, and many patients do not respond well to currently available medications. Attempts to find risk factors for the disorder using epidemiological methods have shown that schizophrenia is highly heritable, and path analyses predict that the disorder is caused by several genes in combination with nongenetic factors. Therefore, intensive research efforts have been made to identify genes creating vulnerability to schizophrenia and also genes predicting response to treatment. Interactions of the glutamatergic system with dopaminergic and serotonergic circuitry are crucial for normal brain function, and their disruption may be a mechanism by which the pathophysiology of schizophrenia is manifest. Genes within the glutamatergic system are therefore strong candidates for investigation, and these include the glutamate receptor genes in addition to genes encoding neuregulin, dysbindin, D-amino acid oxidase and G72/G30. These genetic studies could eventually reveal new targets for antipsychotic drug treatment, which currently focuses on inhibition of the dopaminergic system. However, a recent breakthrough indicates clinical efficacy of a drug stimulating the metabotropic glutamate receptor II, LY2140023, which has improved efficacy for negative and cognitive symptoms of schizophrenia. Studies of larger patient samples are required to consolidate these data. Further investigation of glutamatergic targets is likely to reinvigorate antipsychotic drug development.
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PMID:Role of glutamate in schizophrenia: integrating excitatory avenues of research. 1875 51

Perturbations in neuregulin-1 (NRG1)/ErbB4 function have been associated with schizophrenia. Affected patients exhibit altered levels of these proteins and display hypofunction of glutamatergic synapses as well as altered neuronal circuitry. However, the role of NRG1/ErbB4 in regulating synapse maturation and neuronal process formation has not been extensively examined. Here we demonstrate that ErbB4 is expressed in inhibitory interneurons at both excitatory and inhibitory postsynaptic sites. Overexpression of ErbB4 postsynaptically enhances size but not number of presynaptic inputs. Conversely, knockdown of ErbB4 using shRNA decreases the size of presynaptic inputs, demonstrating a specific role for endogenous ErbB4 in synapse maturation. Using ErbB4 mutant constructs, we demonstrate that ErbB4-mediated synapse maturation requires its extracellular domain, whereas its tyrosine kinase activity is dispensable for this process. We also demonstrate that depletion of ErbB4 decreases the number of primary neurites and that stimulation of ErbB4 using a soluble form of NRG1 results in exuberant dendritic arborization through activation of the tyrosine kinase domain of ErbB4 and the phosphoinositide 3-kinase pathway. These findings demonstrate that NRG1/ErbB4 signaling differentially regulates synapse maturation and dendritic morphology via two distinct mechanisms involving trans-synaptic signaling and tyrosine kinase activity, respectively.
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PMID:ErbB4-neuregulin signaling modulates synapse development and dendritic arborization through distinct mechanisms. 1881 24

Neuregulin-1 (NRG-1) is genetically linked with schizophrenia, a neurodevelopmental cognitive disorder characterized by imbalances in glutamatergic and dopaminergic function. NRG-1 regulates numerous neurodevelopmental processes and, in the adult, suppresses or reverses long-term potentiation (LTP) at hippocampal glutamatergic synapses. Here we show that NRG-1 stimulates dopamine release in the hippocampus and reverses early-phase LTP via activation of D4 dopamine receptors (D4R). NRG-1 fails to depotentiate LTP in hippocampal slices treated with the antipsychotic clozapine and other more selective D4R antagonists. Moreover, LTP is not depotentiated in D4R null mice by either NRG-1 or theta-pulse stimuli. Conversely, direct D4R activation mimics NRG-1 and reduces AMPA receptor currents and surface expression. These findings demonstrate that NRG-1 mediates its unique role in counteracting LTP via dopamine signaling and opens future directions to study new aspects of NRG function. The novel functional link between NRG-1, dopamine, and glutamate has important implications for understanding how imbalances in Neuregulin-ErbB signaling can impinge on dopaminergic and glutamatergic function, neurotransmitter pathways associated with schizophrenia.
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PMID:Neuregulin-1 regulates LTP at CA1 hippocampal synapses through activation of dopamine D4 receptors. 1883 54

To a large extend schizophrenia has been shown to be heritable, with neuregulin-1 (NRG1) one of the candidate genes considered to play a role in the pathophysiology of the disorder. While several polymorphisms within this gene have been reported to be associated with schizophrenia, the impact of NRG1 risk genotypes on disturbed brain function and symptoms of the disease is unknown and might be elucidated using post-mortem studies. Neuregulins are signalling proteins and the NRG1 family encodes at least 15 different splice variants, classified into four isoforms. They play an important role in cell differentiation, migration, myelination and proliferation of oligodendrocytes and neurons. Dysfunction in these processes may be related to neurodevelopmental disturbances in schizophrenia. NRG1 isoforms are differentially expressed in relevant brain regions of schizophrenia patients such as the prefrontal cortex and hippocampus and may contribute to pathophysiological processes. Different NRG1 genotypes have been shown to influence gene expression of isoforms and the risk-associated variants are in primarily non-coding and promoter regions, probably operating by altering gene expression or splicing. In addition, NRG1 regulates the expression of the nicotinic acetylcholine receptor, and expression of the gamma-aminobutyric acid (GABA(A)) and N-methyl-D: -aspartate receptor in the brain. However, the contribution of NRG1 risk genotypes to expression of isoforms and cognitive or psychotic symptoms in patients remain to be investigated in prospective post-mortem studies. In animal models of ischemia/hypoxia, NRG1 has been shown to act as a therapeutic, neuroprotective agent and should be investigated in more detail in transgenic animal models.
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PMID:Impact of neuregulin-1 on the pathophysiology of schizophrenia in human post-mortem studies. 1898 92


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