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)

Because amphetamine releases two to three times more dopamine in schizophrenia patients than in control subjects, and because calcium-calmodulin-dependent protein kinase II has a key role in the enhanced action of amphetamine-induced dopamine release in rats, the synaptic content of calcium-calmodulin-dependent protein kinase IIbeta mRNA was measured (by quantitative competitive RT-PCR; reverse transcriptase-polymerase chain reaction) in seven frontal cerebral cortices of post-mortem brains from patients who had schizophrenia and in seven control tissues. The results indicate that the mRNA of this kinase is elevated in the schizophrenia frontal cortex.
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PMID:Schizophrenia: elevated mRNA for calcium-calmodulin-dependent protein kinase IIbeta in frontal cortex. 1104 61

Calcineurin (CN), a calcium- and calmodulin-dependent protein phosphatase, plays a significant role in the central nervous system. Previously, we reported that forebrain-specific CN knockout mice (CN mutant mice) have impaired working memory. To further analyze the behavioral effects of CN deficiency, we subjected CN mutant mice to a comprehensive behavioral test battery. Mutant mice showed increased locomotor activity, decreased social interaction, and impairments in prepulse inhibition and latent inhibition. In addition, CN mutant mice displayed an increased response to the locomotor stimulating effects of MK-801. Collectively, the abnormalities of CN mutant mice are strikingly similar to those described for schizophrenia. We propose that alterations affecting CN signaling could comprise a contributing factor in schizophrenia pathogenesis.
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PMID:Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia. 1285 57

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

Clinical and experimental evidence suggest an involvement of dopamine systems, mainly the mesocorticolimbic one (MCL), in Attention-Deficit Hyperactivity Disorder (ADHD). However, it remains to be ascertained whether the systems are hyper- or hypo-functioning, for the implications of the functional state. Indeed, differential functional states of the MCL branches are suggested to be the neural substrate of different ADHD variants. This review covers published and unpublished data from the Naples-High Excitability (NHE) rat, an animal model of ADHD, featuring its main aspects, with no hypertension. Therefore, a multiple approach based on morphological studies of dopamine, norepinephrine, glutamate, acetylcholine and GABA systems, synaptic (Calcium/Calmodulin kinase II) and extrasynaptic (chondroitin sulphates) environments, and molecular biology and pharmacological studies on the dopamine system has been carried out. Morphological findings suggest dopamine neurons in the Ventral Tegmental Area (VTA) to be hypertrophic in NHE rats. The mesostriatal and mesolimbic dopamine branches appear to be normal in basal conditions. However, the striatal interface is probably defective following activation. Conversely, the prefrontal cortex, which represents the second main target of VTA dopamine neurons, has many alterations at the basal level. Therefore, the emerging picture is the association of a hyperinnervating and hyperfunctioning mesocortical branch of the dopamine system. Thus, the evidence gathered so far might improve our understanding of the neural substrates of neuropsychiatric disorders such as ADHD, schizophrenia and drug addiction.
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PMID:Behavioural, pharmacological, morpho-functional molecular studies reveal a hyperfunctioning mesocortical dopamine system in an animal model of attention deficit and hyperactivity disorder. 1462 12

In most central neurons, small conductance Ca(2+)-activated K(+) channels (SK channels) contribute to afterhyperpolarizations (AHPs), which control neuronal excitability. The medium AHP has pharmacological properties similar to recombinant SK channels, consistent with the hypothesis that SK channels generate this afterhyperpolarization component. It is still unclear how recombinant SK channels are functionally related to the slow AHP component. Cloned SK channels are heteromeric complexes of SK channel subunits and calmodulin. The channels are activated by Ca(2+) binding to calmodulin that induces conformational changes resulting in channel opening. Channel deactivation is the reverse process brought about by dissociation of Ca(2+) from calmodulin. In the mammalian brain, the three SK channel subunits (SK1-3) display partially overlapping distributions. Most of the higher brain regions such as the neocortex and hippocampus show expression of both genes encoding SK1 and SK2 channels, whereas phylogenetically older brain regions such as the thalamus, basal ganglia, cerebellum, and brainstem show high levels of SK3 gene expression. At present, it is still unclear whether native SK channels are generated as heteromeric or homomeric channels. Peptide toxins such as apamin and scyllatoxin, as well as organic compounds such as quaternary salts of bicuculline, dequalinium, UCL 1684 and UCL 1848 serve as non-specific SK channel blockers. The only known exceptions so far are the scorpion toxin tamapin and the peptide inhibitor Lei-Dab(7), which bind preferentially to SK2. Electrophysiological and behavioral studies indicate that blockade of SK channels by apamin increases excitability, lowers the threshold for the induction of synaptic plasticity, and facilitates hippocampus-dependent memory. The potential value of pharmacological SK channel modulation in various pathological states such as increased epileptiform activity, cognitive impairment, pain, mood disorders and schizophrenia will be discussed.
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PMID:Small conductance Ca2+-activated K+ channels as targets of CNS drug development. 1518 Apr 77

Calcineurin (CaN), also designated as protein phosphatase 2B, is a major Ca2+/calmodulin-binding protein in the brain and the only serine/threonine phosphatase under the control of Ca2+/calmodulin. CaN activity has been implicated in downstream regulation of dopaminergic signal transduction and in NMDA receptor-dependent synaptic plasticity. Thus, it serves as a point of convergence for the abnormalities of these two neurotransmitter systems in schizophrenia. The aim of the present study was to determine if levels of CaN were altered in two schizophrenia- and CaN-related brain regions--the dorsolateral prefrontal cortex and hippocampus from subjects with schizophrenia compared to that in tissue from age and sex matched controls. CaN protein levels were measured by Western-blot analysis in samples from 15 schizophrenia patients vs. 15 control subjects. No significant differences in CaN protein levels were found either in the prefrontal cortex or in the hippocampus of schizophrenia patients compared to matched control subjects. Our result of lack of difference does not support the concept that brain CaN levels are a pathophysiological factor in this disorder. Further studies with antibodies against specific CaN catalytic subunit isoforms (presently unavailable) are required to resolve this issue.
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PMID:Postmortem brain calcineurin protein levels in schizophrenia patients are not different from controls. 1646 Sep 15

Schizophrenia is a complex and poorly understood neuropsychiatric disorder. Much research has begun to implicate the prefrontal cortex in the disease. Using immunocytochemistry we determined if neurogranin, a protein found in dendrites, spines and cell bodies and an upstream regulator of calcium was altered in areas 9 and 32 of schizophrenic prefrontal cortex. We examined its expression in pyramidal cells in layers III and V. Tissues from 7 controls and 7 schizophrenics (from our original MAP2 study, Jones, L., Johnson, N., Byne, W., 2002. Alterations in MAP2 staining in area 9 and 32 of schizophrenic prefrontal cortex. Psych. Res. 114, 137-148) matched for age, sex and postmortem interval were examined. Using area fraction analysis we quantified the immunostaining. Additionally, we counted the number of positively stained pyramidal cells in the same 7 pairs. Neurogranin immunostaining was dramatically reduced in both layers III (72%) and V (50%) in area 9. In area 32 there was a more modest reduction in both layers III (36%) and V (40%). There was no difference in either brain region or layer in the density of positively stained pyramidal cells. These data confirm mounting evidence suggesting dendritic loss in the prefrontal cortex and suggest that the loss of protein does not appear to be due to a change in the number of cells producing the protein but rather in the amount of protein being produced. Additionally, these data suggest that the loss of neurogranin may alter the calcium-calmodulin dependent pathways due to its role as a regulator of calmodulin suggesting a link between structural and functional alterations of the pyramidal cells in the prefrontal cortex.
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PMID:Evidence of altered neurogranin immunoreactivity in areas 9 and 32 of schizophrenic prefrontal cortex. 1679 25

The neurogranin (NRGN) gene produces a postsynaptic brain-specific protein that regulates calmodulin-Ca(2+) availability in neurons. Acting downstream of the NMDA receptor and upstream of calcineurin and other proteins implicated in schizophrenia, NRGN is a good candidate for association studies in schizophrenia. NRGN expression is regulated during development and is modulated by thyroid hormones and retinoids, molecules essential for the proper development of the central nervous system. Given the genetic complexity of schizophrenia and the potential genetic heterogeneity in different populations, we studied a possible association of NRGN with schizophrenia in 73 Azorean proband-parent triads and in two independent case-control samples from the Portuguese-mainland (244 schizophrenic and 210 controls) and Brazil (69 schizophrenic and 85 mentally healthy individuals). Genotype distribution showed association of the rs7113041 SNP with schizophrenia in males of Portuguese origin, which was confirmed by the analysis of the proband-parent triads. This evidence, implicating NRGN in schizophrenia, introduces another player into the glutamatergic hypothesis of schizophrenia.
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PMID:Association of the gene encoding neurogranin with schizophrenia in males. 1714 Jun 1

We have been investigating the relationships between genes and behaviors by conducting a systematic and well-defined behavioral test battery with mice that have a mutation on a gene of interest. The behavioral test battery covers a relatively broad range of various behavioral domains such as learning and memory, sensory-motor functions, emotion, motivation, and drug sensitivity/preference. Recently, we subjected mice lacking calcineurin (CN), a calcium/calmodulin protein phosphatase, to the comprehensive behavioral test battery. The mutant mice had a severe working memory deficit, increased locomotor activity, decreased social interaction, and impairments in prepulse and latent inhibition. The abnormalities of CN mutant mice were strikingly similar to those described for schizophrenic patients. Consistent with these findings, human genetics studies in a large sample of affected families detected a significant association of the PPP3CC gene, which encodes the CN gamma catalytic subunit with schizophrenia. The idea that abnormalities in the CN signaling pathway are involved in schizophrenia pathogenesis is consistent with traditional theories of schizophrenia and with many facts known about schizophrenia. A tremendous amount of knowledge about CN has accumulated and, by utilizing this information, the studies on the pathogenesis/pathophysiology of schizophrenia and its related mental disorders will be potentially accelerated. We discuss the potential impact of a large-scale mouse phenotyping project on the study of psychiatric disorders.
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PMID:Investigating gene-to-behavior pathways in psychiatric disorders: the use of a comprehensive behavioral test battery on genetically engineered mice. 1718 13

In humans, phencyclidine (PCP), a noncompetitive N-methyl-d-aspartate (NMDA) antagonist, reproduces a schizophrenia-like psychosis such as positive/negative symptoms and cognitive deficits. PCP (10 mg/kg/day for 14 days)-treated mice exhibit the enhanced immobility in a forced swimming test as indexes of negative symptoms and impairment of latent learning in a water finding test as indexes of cognitive deficits. These behavioral deficits remain after withdrawal from repeated PCP treatment and are attenuated by atypical antipsychotics, but not by typical antipsychotics. Since it has been hypothesized that insufficient glutamate neurotransmission is involved in the pathophysiology of schizophrenia, we investigated an involvement of glutamatergic system in emotional and cognitive deficits in mice treated with PCP repeatedly. Ca(2+)/calmodulin kinase II (CaMKII) is markedly phosphorylated after the forced swimming test and the training trial of water finding test in the prefrontal cortex of saline-treated mice but not PCP-treated mice. Facilitation of NMDA receptor function by NMDA receptor glycine-site agonists such as D-cycloserine and glycine is effective on the abnormal intracellular signaling, and emotional and cognitive deficits in mice treated with PCP repeatedly. The repeated PCP treatment impaired NMDA receptor function and decreased levels of spontaneous extracellular glutamate in the prefrontal cortex, indicating that the repeated PCP treatment impairs both pre- and postsynaptic glutamate transmissions. Our findings suggest that abnormal NMDA receptor signaling is involved in the emotional and cognitive deficits in mice treated with PCP repeatedly. Our PCP-treated mice would be a useful model for studying the effect of antipsychotics on emotional and cognitive deficits in schizophrenia.
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PMID:Animal model of schizophrenia: dysfunction of NMDA receptor-signaling in mice following withdrawal from repeated administration of phencyclidine. 1718 14


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