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

Neuregulin-1 (NRG-1) has been identified genetically as a schizophrenia susceptibility gene, but its function in the adult brain is unknown. Here, we show that NRG-1beta does not affect basal synaptic transmission but reverses long-term potentiation (LTP) at hippocampal Schaffer collateral-->CA1 synapses in an activity- and time-dependent manner. Depotentiation by NRG-1beta is blocked by two structurally distinct and selective ErbB receptor tyrosine kinase inhibitors. Moreover, ErbB receptor inhibition increases LTP at potentiated synapses and blocks LTP reversal by theta-pulse stimuli. NRG-1beta selectively reduces AMPA, not NMDA, receptor EPSCs and has no effect on paired-pulse facilitation ratios. Live imaging of hippocampal neurons transfected with receptors fused to superecliptic green fluorescent protein, as well as quantitative analysis of native receptors, show that NRG-1beta stimulates the internalization of surface glutamate receptor 1-containing AMPA receptors. This novel regulation of LTP by NRG-1 has important implications for the modulation of synaptic homeostasis and schizophrenia.
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PMID:Neuregulin-1 reverses long-term potentiation at CA1 hippocampal synapses. 1622 46

In the central nervous system (CNS), neuregulin-1 (NRG-1) proteins function in neuronal migration, differentiation, and survival of oligodendrocytes. The NRG-1 gene codes for at least 15 different isoforms, which may be classified on the basis of their molecular structure. At least two different haplotypes of the NRG-1 gene may be associated with schizophrenia. An abnormal expression pattern of NRG-1 mRNA was found in the prefrontal cortex of schizophrenic patients in comparison to controls. We here show that the NRG-1alpha isoform is significantly reduced in white matter of the prefrontal cortex in schizophrenia but not in affective disorder. In the prefrontal gray matter, the density of NRG-1alpha expressing neurons was reduced in individuals with schizophrenia and in unipolar patients. We studied brains of 22 schizophrenics, 12 patients with affective disorders (7 unipolar and 5 bipolar), and 22 matched controls. NRG-1alpha immunoreactive material was detected with a polyclonal antiserum against the synthetic peptide from alpha-type EGF-like domain of human NRG. The demonstrated decreased number of NRG-1 immunoreactive neurons in the brains of schizophrenics and patients with unipolar depression points to an important role of this NRG-1alpha splice variant in neuropsychiatric disorders. Reduced NRG-1alpha protein concentrations were found in brains of schizophrenics after Western blot analysis. The diminished expression of NRG-1alpha strongly supports an early neurodevelopmental component to schizophrenia.
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PMID:Immunohistochemical evidence for impaired neuregulin-1 signaling in the prefrontal cortex in schizophrenia and in unipolar depression. 1740 26

Neuregulin-1 (NRG-1), a replicated gene in schizophrenia-association studies, exhibits six mRNA-types and two types of the EGF-like domain, alpha and beta. The beta-isoform was extensively studied, less is known about the extent and specific localization of adult brain NRG-1alpha. NRG-1alpha protein levels were reported reduced in postmortem prefrontal-cortex of schizophrenia patients. NRG-1 type I mRNA levels were found higher in postmortem brain in schizophrenia. In an attempt to decipher between a genetic or environmental involvement in the differences in NRG-1 levels in postmortem brain in schizophrenia, and since obstetric complications were suggested non-genetic risk-factors of schizophrenia, we studied the effect of perinatal hypoxia in rats on brain NRG-1alpha protein levels. Seven-day-old rats were exposed to hypoxia versus air. Frontal-cortex levels of NRG-1alpha isoform were quantified at adulthood by Western blotting. Frontal-cortex NRG-1alpha was 32% elevated in hypoxia-exposed rats. The data support the role of non-genetic factors, e.g. oxygen restriction, in the expression of genes associated with schizophrenia.
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PMID:Oxygen restriction of neonate rats elevates neuregulin-1alpha isoform levels: possible relationship to schizophrenia. 1763 47

Polymorphisms in the Neuregulin 1 (NRG1) and ErbB4 receptor genes have been associated with schizophrenia in numerous cohort and family studies, and biochemical measurements from postmortem prefrontal cortex homogenates suggest that NRG/ErbB signalling is altered in schizophrenia. Moreover, recent work from our group, and from others, indicates that NRG/ErbB signalling has a role in regulating glutamatergic transmission--an intriguing finding given that glutamatergic hypofunction has been proposed to be involved in the pathogenesis underlying schizophrenia. Here we will provide a brief background of the complexity of the NRG/ErbB signalling system. We will then focus on how NRG1 reverses (depotentiates) long-term potentiation (LTP) at hippocampal Schaeffer collateral--CA1 glutamatergic synapses in the adult brain. Specifically, we found that NRG1 depotentiates LTP in an activity- and time-dependent manner. A role of endogenous NRG for regulating plasticity at hippocampal synapses is supported by experiments demonstrating that ErbB receptor antagonists completely block LTP depotentiation by brief theta-pulse stimuli, a subthreshold stimulus paradigm that reverses LTP in live animals. Preliminary results indicate that NRG1-mediated LTP depotentiation is NMDA receptor independent, and manifests as an internalization of GluR1-containing AMPA receptors. The importance of the NRG/ ErbB signalling pathway in regulating homeostasis at glutamatergic synapses, and its possible implications for schizophrenia, will be discussed.
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PMID:Neuregulins and neuronal plasticity: possible relevance in schizophrenia. 1849 2

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

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

NRG1 (neuregulin 1) belongs to the NRG family of EGF (epidermal growth factor)-like signalling molecules involved in cell-cell communication during development and disease. It plays important roles in the developing tissues of the nerves, heart and mammary glands. Particularly in neurobiology, NRG1 signalling is associated with synaptic transmission, myelination of Schwann cells and the human disease of schizophrenia. Many different isoforms of NRG1 make the molecule highly sophisticated in biological activities and a great diversity of in vivo functions. The nervous system is a common trait in all bilateria (higher animals), but based on the BLAST information from the currently available databases it appears that NRG1 orthologues can only be identified in vertebrates. The gene was analysed in silico for type I-IV CDSs (coding sequences) from ten vertebrate genomes. The gene loci, structures of coding-intronic sequences, ClustalW program analyses, phylogenetic trees and conserved motifs in ecto- and cyto-plasmic domains were analysed and compared. Here, we conclude that non-mammalian vertebrates mainly carry type I (may have evolved a spacer different from mammalian isoforms), II and III NRG1s. The type IV NRG1 N-terminal CDSs can be identified from most of the mammalian genomes studied; however, the corresponding rodent sequences lack the start codon. The evolutionary conservation of a CDS59-CDS24-CDS103 domain, intracellular phosphorylation sites and bipartite nuclear localization signals is of physiological significance.
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PMID:In silico analysis of neuregulin 1 evolution in vertebrates. 1968 57

Neuregulin 1 (NRG1) is a pleiotropic growth factor involved in diverse aspects of brain development and function. In schizophrenia, expression of the NRG1 type I isoform is selectively increased. However, virtually nothing is known about the roles of this isoform in brain. We have studied transgenic mice overexpressing type I NRG1(NRG1type 1-tg) using a series of behavioural tests. NRG1(type 1-tg) mice have a tremor, are impaired on the accelerating rotarod, and have reduced prepulse inhibition in the context of an increased baseline startle response. There is no overall anxiety or activity phenotype, although female NRG(1type 1-tg) mice show mild increases in anxiety on some measures. The pattern of results shows both similarities and differences to those reported in hypomorphic NRG1 mice, and may be relevant for interpreting the increased NRG1 type I expression observed in schizophrenia.
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PMID:Behavioural characterization of neuregulin 1 type I overexpressing transgenic mice. 1982 62

Neuregulin-1 (NRG1) and Disrupted-in-Schizophrenia-1 (DISC1) are promising susceptibility factors for schizophrenia. Both are multifunctional proteins with roles in a variety of neurodevelopmental processes, including progenitor cell proliferation, migration, and differentiation. Here, we provide evidence linking these factors together in a single pathway, which is mediated by ErbB receptors and PI3K/Akt. We show that signaling by NRG1 and NRG2, but not NRG3, increase expression of an isoform of DISC1 in vitro. Receptors ErbB2 and ErbB3, but not ErbB4, are responsible for transducing this effect, and PI3K/Akt signaling is also required. In NRG1 knockout mice, this DISC1 isoform is selectively reduced during neurodevelopment. Furthermore, a similar decrease in DISC1 expression is seen in beta-site amyloid precursor protein cleaving enzyme-1 (BACE1) knockout mice, in which NRG1/Akt signaling is reportedly impaired. In contrast to neuronal DISC1 that was reported and characterized, expression of DISC1 in other types of cells in the brain has not been addressed. Here we demonstrate that DISC1, like NRG and ErbB proteins, is expressed in neurons, astrocytes, oligodendrocytes, microglia, and radial progenitors. These findings may connect NRG1, ErbBs, Akt, and DISC1 in a common pathway, which may regulate neurodevelopment and contribute to susceptibility to schizophrenia.
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PMID:Disrupted-in-Schizophrenia-1 expression is regulated by beta-site amyloid precursor protein cleaving enzyme-1-neuregulin cascade. 2021 27

Linkage of 10q22-q23 to schizophrenia and the recently reported association of Neuregulin 3 (NRG3) polymorphisms with high 'delusion factor' scores led us to attempt replication and further refinement of these findings in a sample of 411 schizophrenic patients and 223 nonpsychiatric control subjects. Using quantitative cognitive traits, patients were grouped into a cluster with pervasive cognitive deficit (CD) and a cluster with relatively spared cognition (CS). We found a significant association between rs6584400 and schizophrenia, with a trend for rs10883866. Post hoc analysis revealed that this result was mainly due to the CS cluster, characterized by elevated scores on Schneiderian first-rank symptoms, salience of complex delusions and positive thought disorder--thus closely related to the 'delusion factor'. In addition, both rs6584400 and rs10883866 were associated with the degraded-stimulus continuous performance task in which 'risk' alleles were associated with better than average performance in patients and worse performance in controls. This suggests that NRG3 may be modulating early attentional processes for perceptual sensitivity and vigilance, with opposite effects in affected individuals and healthy controls. The two single-nucleotide polymorphisms are in close proximity to the alternative first exons of the NRG3-a, -b and -d isoforms, of which the human brain-specific NRG-b appears to be the most interesting candidate.
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PMID:Neuregulin 3 (NRG3) as a susceptibility gene in a schizophrenia subtype with florid delusions and relatively spared cognition. 2054 96


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