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)

Fasciculation and elongation protein zeta-1 (FEZ1) is a mammalian homologue of the Caenorhabditis elegans UNC-76 protein involved in axonal outgrowth and fasciculation. Recently, we reported that FEZ1 interacts with Disrupted-In-Schizophrenia 1 (DISC1), a product of the candidate gene for schizophrenia, and that the interaction between these proteins has a role in neurite outgrowth. This time, we investigated the expression of FEZ1 and DISC1 in the developing rat brain using in situ hybridization. Both FEZ1 and DISC1 showed high levels of expression, especially in developing hippocampal neurons. These findings suggest the potential involvement of FEZ1 and DISC1 in the formation of hippocampal neural circuits.
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PMID:Expression of fasciculation and elongation protein zeta-1 (FEZ1) in the developing rat brain. 1499 19

The conceptualization of schizophrenia as a disorder of connectivity, i.e., of neuronal?synaptic plasticity, suggests abnormal synaptic modeling and neuronal signaling, possibly as a consequence of flawed interactions with the environment, as at least a secondary mechanism underlying the pathophysiology of this disorder. Indeed, deficits in episodic memory and malfunction of hippocampal circuitry, as well as anomalies of axonal sprouting and synapse formation, are all suggestive of diminished neuronal plasticity in schizophrenia. Evidence supports a dysfunction of mitochondria in schizophrenia, including mitochondrial hypoplasia, and a dysfunction of the oxidative phosphorylation system, as well as altered mitochondrial-related gene expression. Mitochondrial dysfunction leads to alterations in ATP production and cytoplasmatic calcium concentrations, as well as reactive oxygen species and nitric oxide production. All of the latter processes have been well established as leading to altered synaptic strength or plasticity. Moreover, mitochondria have been shown to play a role in plasticity of neuronal polarity, and studies in the visual cortex show an association between mitochondria and synaptogenesis. Finally, mitochondrial gene upregulation has been observed following synaptic and neuronal activity. This review proposes that mitochondrial dysfunction in schizophrenia could cause, or arise from, anomalies in processes of plasticity in this disorder.
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PMID:Mitochondria, synaptic plasticity, and schizophrenia. 1500 92

The dopamine D2 receptor (D2R) in the nucleus accumbens (NAc) shell is implicated in schizophrenia and in psychostimulant-induced drug-seeking behavior, both of which are affected by activation of the functionally opposed high-affinity neurotensin receptor (NTS1). To determine the functionally relevant sites, we examined the dual electron microscopic immunocytochemical localization of D2R and NTS1 in the NAc shell of rat brain. Immunolabeling for each receptor was seen in association with cytoplasmic organelles, or more rarely, on the plasma membrane of both axonal and somatodendritic profiles. Some of the axonal and many of the dendritic processes colocalized the two receptors. The dually labeled axon terminals often formed symmetric synapses or appositional contacts with unlabeled dendritic profiles. The morphology of these terminals suggests that they contain either inhibitory amino acids or dopamine. Other axonal profiles expressing exclusively NTS1 or D2R were without synaptic specializations or formed asymmetric, excitatory-type synapses mainly on unlabeled dendritic spines. In addition, however, several D2R-immunoreactive terminals were observed presynaptic to dendrites containing NTS1. The somatodendritic profiles immunolabeled for NTS1 and/or D2R had morphological features typical of inhibitory spiny projection neurons in the NAc. These results suggest that activation of NTS1 and D2R can dually modulate transmitter release from the same or separate phenotypically distinct axon terminals in the NAc shell. These presynaptic receptors as well as the postsynaptic NTS1 distribution in neurons that also contain or receive input from terminals containing D2R may mediate the opposing actions of neurotensin and dopamine in the NAc.
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PMID:Electron microscopic dual labeling of high-affinity neurotensin and dopamine D2 receptors in the rat nucleus accumbens shell. 1506 18

Major depressive disorder is one of the most common and devastating psychiatric disorders. To identify candidate mechanisms for major depressive disorder, we compared gene expression in the temporal cortex from 12 patients with major depressive disorder and 14 matched controls using Affymetrix HgU95A microarrays. Significant expression changes were revealed in families of genes involved in neurodevelopment, signal transduction and cell communication. Among these, the expression of 17 genes related to oligodendrocyte function was significantly (P < 0.05, fold change > 1.4) decreased in patients with major depressive disorder. Eight of these 17 genes encode structural components of myelin (CNP, MAG, MAL, MOG, MOBP, PMP22, PLLP, PLP1). Five other genes encode enzymes involved in the synthesis of myelin constituents (ASPA, UGT8), or are essential in regulation of myelin formation (ENPP2, EDG2, TF, KLK6). One gene, that is, SOX10, encodes a transcription factor regulating other myelination-related genes. OLIG2 is a transcription factor present exclusively in oligodendrocytes and oligodendrocyte precursors. Another gene, ERBB3, is involved in oligodendrocyte differentiation. In addition to myelination-related genes, there were significant changes in multiple genes involved in axonal growth/synaptic function. These findings suggest that major depressive disorder may be associated with changes in cell communication and signal transduction mechanisms that contribute to abnormalities in oligodendroglia and synaptic function. Taken together with other studies, these findings indicate that major depressive disorder may share common oligodendroglial abnormalities with schizophrenia and bipolar disorder.
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PMID:Transcriptional profiling reveals evidence for signaling and oligodendroglial abnormalities in the temporal cortex from patients with major depressive disorder. 1530 2

Schizophrenia (SCZD) or schizoaffective disorders are quite common features in patients with DiGeorge/velo-cardio-facial syndrome (DGS/VCFS) as a result of chromosome 22q11.2 aploinsufficiency. We evaluated the Nogo-66 receptor gene (RTN4R), which maps within the DGS/VCFS critical region, as a potential candidate for schizophrenia susceptibility. RTN4R encodes for a functional cell surface receptor, a glycosylphosphatidylinositol (GPI)-linked protein, with multiple leucine-rich repeats (LRR), which is implicated in axonal growth inhibition. One hundred and twenty unrelated Italian schizophrenic patients were screened for mutations in the RTN4R gene using denaturing high performance liquid chromatography (DHPLC). Three mutant alleles were detected, including two missense changes (c.355C>T; R119W and c.587G>A; R196H), and one synonymous codon variant (c.54G>A; L18L). The two schizophrenic patients with the missense changes were strongly resistant to the neuroleptic treatment at any dosage. Both missense changes were absent in 300 control subjects. Molecular modeling revealed that both changes lead to putative structural alterations of the native protein.
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PMID:Mutations of the Nogo-66 receptor (RTN4R) gene in schizophrenia. 1553 24

The cytoskeleton plays a key role in maintaining the highly asymmetrical shape and structural polarity of neurons that are essential for neuronal physiology. Cytoskeletal reorganization plays a key role in neuritogenesis. In neurodegenerative diseases, the cytoskeleton is abnormally assembled and impairment of neurotransmission occurs. In Alzheimer's disease, abundant amyloid plaques and neurofibrillary tangles constitute the two major neuropathologic alterations present in the brain. Neurofibrillary tangles are formed of paired helical filaments consisting nearly entirely of the microtubule-associated protein tau. Under normal conditions tau binds to microtubules, stabilizing neuron structure and integrity. Hyperphosphorylation of tau is assumed to be the cause of formation of paired helical filaments. Another example of cytoskeletal abnormalities present in neurodegenerative diseases are the Lewy bodies considered as cytopathologic markers of Parkinson's disease. Lewy bodies are constituted of tubulin, MAP1, and MAP2. Neuronal shape, loss of dendrites and spines, as well as irregular distribution of neuronal elongations occur in specific brain areas of schizophrenic patients. Increase in non-phosphorylated MAP2 and MAP1B at hippocampus has been suggested as responsible for somatodendritic and cytoarchitectural abnormalities found in schizophrenia. In addition, neurofibrillary tangles are more frequent among schizophrenic patients who received pharmacologic antipsychotic treatment. Cumulative evidence suggests that neurodegenerative diseases and psychiatric illnesses are associated with cytoskeletal alterations in neurons that, in turn, loose synaptic connectivity and the ability to transmit incoming axonal information to the somatodendritic domain. We will review evidence supporting that the neuronal cytoskeleton is disrupted in neurodegenerative and some psychiatric diseases, and therefore could be a target for drug therapy. In addition, current data indicating that melatonin, a hormone secreted by the pineal gland, promotes neuritogenesis through cytoskeletal rearrangements and in addition to the potential therapeutic use of melatonin in neurodegenerative diseases will be discussed.
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PMID:The neuronal cytoskeleton as a potential therapeutical target in neurodegenerative diseases and schizophrenia. 1558 21

Chandelier neurons and their characteristic arrays of axonal terminals, known as cartridges, have been implicated in a variety of psychiatric and neurological disorders including schizophrenia and epilepsy. As a result, these neurons have been extensively examined in the brains of several species using a range of markers. However, these markers have not been systematically compared in a single species for their robustness in labelling chandelier cell cartridges. We have therefore examined several markers, reported to label chandelier arrays in primates, for their capacity to mark these structures in rat medial prefrontal cortex and hippocampus. These studies revealed that cartridge-like structures were labelled by parvalbumin and GAT-1 immunohistochemistry in both medial prefrontal cortex and hippocampus of the rat brain. Additionally, GAD65 immunohistochemistry labelled array-like structures preferentially in the dentate gyrus. In contrast, PSA-NCAM, calbindin and GAD67 immunohistochemistry did not reveal any array-like structures in either region of rat brain. These observations indicate that the various immunological markers previously used to visualise chandelier cell cartridges in primates are not equally efficient in labelling these structures in the rat brain, and that GAT-1 immunohistochemistry is the most robust means of visualising chandelier cell cartridges in the regions examined. These are important considerations for quantitative studies in animal models of neurological disorders where chandelier neurons are implicated.
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PMID:A comparison of possible markers for chandelier cartridges in rat medial prefrontal cortex and hippocampus. 1564 49

Many of the functions that are mediated by the prefrontal cortex (PFC) are severely impaired in schizophrenia. The maturation of these functions takes place during late adolescence and early adulthood, which coincides with the period of time when overt symptomatology of schizophrenia most commonly emerges. Two developmental processes occurring during the periadolescence period appear to mediate the functional maturation of the PFC: pruning of exuberant synapses and myelination of axons. It has long been speculated in the literature that disturbances of these processes may result in dysfunction of the PFC and thereby trigger the emergence of symptoms and deficits of schizophrenia. Alternatively, but not mutually exclusively, it has also been suggested that these late developmental processes may not be aberrant but they "unmask" preexisting deficits in the PFC, resulting in the onset of symptoms. The important implication of both of these scenarios is that in either case the emergence of PFC functional disturbances and the onset of symptoms and deficits of schizophrenia would in theory be preventable by pharmacologic manipulation of the synaptic pruning and/or axonal myelination processes. Thus, better understanding of the cellular and molecular mechanisms that mediate these processes will provide truly novel insight into the therapeutics and prevention of schizophrenia.
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PMID:Targeting synapses and myelin in the prevention of schizophrenia. 1565 62

The close homolog of L1 (CHL1), located on human chromosome 3p26.1, is a newly identified member of the L1 family of cell adhesion molecules which play important roles in cell migration, axonal growth, and synaptic remodeling. A positive association has been reported between a missense polymorphism in CHL1 gene and schizophrenia in the Japanese population [Sakurai, K., Migita, O., Toru, M., Arinami, T., 2002. An association between a missense polymorphism in the close homologue of L1 (CHL1, CALL) gene and schizophrenia. Mol. Psychiatry 7, 412-415]. An association between a missense polymorphism in the close homologue of L1 (CHL1, CALL) gene and schizophrenia. In order to test this finding, we genotyped four SNPs in the gene in the Han Chinese population using a sample of 560 cases and 576 controls. Analysis of allele frequencies in both samples also showed strong association between SNP rs2272522 (the same marker studied by K. Sakurai) and the disease (X2=31.591, P<0.000001, OR=1.745, 95% CI=1.435-2.121). Our results confirm the positive association between CHL1 gene and schizophrenia and indicate that CHL1 may be involved in the etiology of schizophrenia.
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PMID:Case-control association study of the close homologue of L1 (CHL1) gene and schizophrenia in the Chinese population. 1565 71

A recently developed quantitative model of cortical activity is used that permits data comparison with experiment using a quantitative and standardized means. The model incorporates properties of neurophysiology including axonal transmission delays, synaptodendritic rates, range-dependent connectivities, excitatory and inhibitory neural populations, and intrathalamic, intracortical, corticocortical and corticothalamic pathways. This study tests the ability of the model to determine unique physiological properties in a number of different data sets varying in mean age and pathology. The model is used to fit individual electroencephalographic (EEG) spectra from post-traumatic stress disorder (PTSD), schizophrenia, first episode schizophrenia (FESz), attention deficit hyperactivity disorder (ADHD), and their age/sex matched controls. The results demonstrate that the model is able to distinguish each group in terms of a unique cluster of abnormal parameter deviations. The abnormal physiology inferred from these parameters is also consistent with known theoretical and experimental findings from each disorder. The model is also found to be sensitive to the effects of medication in the schizophrenia and FESz group, further supporting the validity of the model.
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PMID:Neurophysiologically-based mean-field modelling of tonic cortical activity in post-traumatic stress disorder (PTSD), schizophrenia, first episode schizophrenia and attention deficit hyperactivity disorder (ADHD). 1565 79


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