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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Analysis of the neuropathological mutant animals offers us great information on the development and differentiation of the nervous system. I have here introduced two examples of the analyses of the various kinds of neuropathological mutant mice. First one is the mutant mice where Purkinje neurons in the cerebellum are absent. High molecular weight protein, P400, enriched in the Purikinje cells in the cerebellum was greatly decreased in the Purkinje cell deficient mutant mice, nervous, pcd, Lurcher. We demonstrated that P400 is equivalent to IP3 receptor type 1. We found that IP3 receptor type 1 plays an important role in Ca2+ wave in fertilization and long term depression in the cerebellum which is one of the typical example of neuronal plasticity in the cerebellum. Second mutant is reeler mice where neuronal positioning in the brain is abnormal. We found CR50 antigen, reelin is the key molecule as a secreted molecule from Cajal-Retzius neuron for the neuronal positioning. We produced IP3 receptor deficient mice by gene targeting. The birth rate was one fifth of the control and the animals die before 25 postnatal days. They showed cerebellar ataxia and epileptic seizure.
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PMID:[Molecular biological analysis of the development of the mammalian central nervous system]. 957 52

Between 1997 and 2002, 48 data sets from the hippocampus were produced on samples from the Stanley Neuropathology Consortium. From these data sets, 224 total measures were available from the various subdivisions of the hippocampus. An integrative analysis of these measures was performed using a multivariate, nonparametric analysis of variance (ANOVA). ANOVA with correction for multiple comparisons indicated that parvalbumin-containing cells in CA2 were reduced in schizophrenia and bipolar disorder. In addition, reelin protein in the molecular layer of the dentate gyrus was decreased in schizophrenia, bipolar disorder, and depression at the trend level of statistical significance (P=0.065). These results strongly suggest a dysfunction of inhibitory GABA-ergic interneurons in severe mental illness. Without correction for multiple comparisons, 31 measures were abnormal in at least one disease, whereas 11 measures would be expected to appear abnormal by chance. Abnormal molecules included measures of synaptic density or neuronal plasticity (reelin, SNAP-25, BDNF, Complexin I and II), as well as parvalbumin, tyrosine receptor kinase A, glucocorticoid receptors, glutamate NR1 receptor subunits, serotonin 5HT2(A) and 5HT1(B) receptors, and dopamine D(5) receptors.
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PMID:Molecular abnormalities of the hippocampus in severe psychiatric illness: postmortem findings from the Stanley Neuropathology Consortium. 1470 30

The heterozygote reeler mouse (HRM) shows many neuroanatomical and biochemical features that are also present in some human cognitive disorders, such as schizophrenia. In the present study, hippocampal dependent plasticity and cognitive function of the HRM were characterized in detail in an attempt to reveal phenotypic functional differences that result from Reelin haploinsufficiency. The HRM and wild type mice show similar levels of overall activity, coordination, thermal nociception, startle responses, and anxiety-like behavior. In addition, both genotypes show similar shock threshold, identical cued freezing behavior and comparable spatial learning in Morris water maze tasks. However, a significant reduction in contextual fear conditioned learning was observed in the HRM. Electrophysiological studies in hippocampal CA1 synapses revealed a plethora of differences between genotypes. The HRM exhibits reduced field excitatory postsynaptic potentials in responses to similar synaptic inputs, lowered paired pulse facilitation ratio and impaired long-term depression and tetanus-induced long-term potentiation (LTP). Also, deficits were detected in LTP elicited by theta burst stimulation or by a whole cell pairing protocol. These physiologic differences could not be accounted for by changes in the overall amount of glutamate receptor subunits. In addition, it was determined that network-driven excitatory and inhibitory activities recorded in CA1 pyramidal neurons showed that the HRM had comparable amplitude and frequency of spontaneous excitatory postsynaptic currents, but a marked reduction in spontaneous inhibitory postsynaptic currents. Thus, the HRM exhibits a specific hippocampal-dependent learning deficit accompanied with a pronounced impairment of hippocampal plasticity and functional inhibitory innervation.
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PMID:Cognitive disruption and altered hippocampus synaptic function in Reelin haploinsufficient mice. 1637 15

Reelin-deficient mice have been used to investigate the role of this extracellular protein in cortico-striatal plasticity and striatum-related behaviours. Here we show that a repetitive electrical stimulation of the cortico-striatal pathway elicited long-term potentiation (LTP) in homozygous reeler (rl/rl) mice, while causing long-term depression in their wild-type (+/+) littermates. The N-methyl-D-aspartic acid (NMDA) receptor antagonist D-(-)-2 amino-5-phosphonopentanoic acid prevented the induction of LTP in (rl/rl) mice, thus confirming that this form of synaptic plasticity was NMDA receptor-dependent. Interestingly, in the presence of tiagabine, a blocker of gamma-aminobutyric acid (GABA) re-uptake system, the probability that (rl/rl) mice showed LTP decreased significantly, thus suggesting an impaired GABAergic transmission in reeler mutants. Consistent with this view, a decreased density of parvalbumin-positive GABAergic striatal interneurons was found in (rl/rl) mice in comparison to (+/+) mice. Finally, compatible with their abnormal striatal function (rl/rl) mice exhibited procedural learning deficits. Our data, showing alterations in cortico-striatal plasticity largely depending on a depressed GABAergic tone, delineate a mechanism whereby the lack of reelin may affect cognitive functions.
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PMID:Altered cortico-striatal synaptic plasticity and related behavioural impairments in reeler mice. 1706 3

Forty years after the initial discovery of neurogenesis in the postnatal brain of the rat, convincing evidence has been accrued that functional neurons are generated throughout the entire lifespan, particularly in the dentate gyrus (DG) and the subventricular zone (SVZ). This phenomenon has been termed adult neurogenesis (AN) and while it was detected in all examined mammalian species including humans, the physiological role of this process remains unknown. Although a plethora of animal studies indicate an involvement of AN in the pathophysiology of depression, this view has recently kindled considerable controversy. Pertinent studies in humans failed to confirm a role of reduced hippocampal neural stem cell proliferation (NSP) in depression but suggest a contribution to the pathophysiology of schizophrenia. The functional relevance of disturbed AN may encompass erroneous temporal encoding of new memory traces, thereby contributing to cognitive deficits observed in schizophrenia. This AN-hypothesis of schizophrenia is supported by neuroimaging, as well as by several genetically modified rodent models, e.g. reelin and NPAS3 knockout mice. Furthermore, several genes impacting on AN, including NPAS3, were also found to be associated with schizophrenia by case-control studies. In conclusion, several lines of evidence suggest that reduced AN may contribute to the etiopathogenesis of schizophrenic disorders, whereas it does not seem to be a critical risk factor for affective disorders.
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PMID:Neurogenesis and schizophrenia: dividing neurons in a divided mind? 1746 35

Stress is an important risk factor for the emergence of depression, but little is known about the neurobiological mechanisms by which stress might promote depressive symptomatology. Much of the research on this topic has focused on stress-induced changes in hippocampal plasticity, specifically the idea that decreased hippocampal plasticity could be a precipitating factor for depression. Interestingly, recent evidence has described a regulatory role for the extracellular matrix protein reelin in important aspects of neural plasticity within the hippocampus and dentate gyrus. Given this association between reelin and hippocampal plasticity, we investigated whether repeated exposure to corticosterone or physical restraint might decrease reelin expression in specific hippocampal regions. Rats were subjected to either 21 days of corticosterone injections or physical restraint and then sacrificed so that the number of reelin-positive cells throughout the hippocampus and dentate gyrus could be quantified using immunohistochemistry. Our results revealed a significant decrease in the number of reelin-positive cells in the CA1 stratum lacunosum and the subgranular zone of the dentate gyrus in rats that received corticosterone, but not in rats that received restraint. Interestingly, these results parallel our previous observation that corticosterone increases depression-like behavior but physical restraint does not. These novel findings suggest that altered reelin signaling could play a role in the expression of depressive symptomatology after exposure to high levels of glucocorticoids.
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PMID:Repeated exposure to corticosterone, but not restraint, decreases the number of reelin-positive cells in the adult rat hippocampus. 1947 32

An integrative database, Stanley Neuropathology Consortium Integrative Database (SNCID) (http://sncid.stanleyresearch.org), has been developed to facilitate psychiatric research. The SNCID includes 1749 neuropathological markers measured in 12 different brain regions in 60 human subjects (15 each schizophrenia, bipolar disorder, depression, and unaffected controls). Genome-wide expression microarray datasets from three independent studies are also included. Statistical analysis tools such as variance analysis, correlation analysis, and functional annotation tools have been integrated into the database. In this report, we first replicate an earlier correlation analysis between genome-wide expression profiles and an abnormal cytoarchitectural marker using the SNCID. We then show the potential for identifying neuropathological markers that are abnormal in subjects with psychiatric disorders. We also identify biological pathways associated with several abnormal neuropathological markers, including those in the dopamine, glutamate, Reelin, and gamma-aminobutyric acid (GABA)ergic systems. Data exploration using the SNCID may provide insights into the biological pathways associated with the neurotransmitter abnormalities identified in subjects with major psychiatric disorders.
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PMID:The stanley neuropathology consortium integrative database: a novel, web-based tool for exploring neuropathological markers in psychiatric disorders and the biological processes associated with abnormalities of those markers. 1982 93

We examined a potential two-hit murine animal model of depression by assessing whether a genetic deficit in reelin increases vulnerability to the depressogenic effects of the stress hormone corticosterone. Stress is an identified risk factor for the onset of depressive symptoms, but depression also has a significant genetic component, suggesting that environmental factors and genetic background likely interact in the etiology of depression. Previous results have revealed that reelin levels are decreased in post-mortem hippocampal tissue from patients with schizophrenia, bipolar disorder and depression, and also in an animal model of depression. Therefore, we hypothesized that heterozygous reeler mice (HRM), with approximately 50% normal levels of reelin, would be more sensitive to the depressogenic effects of corticosterone than wild-type mice (WTM). Mice received subcutaneous injections of either vehicle or 5 mg/kg, 10 mg/kg, or 20 mg/kg of corticosterone for 21 consecutive days, and then they were assessed for changes in depression-like behavior, hippocampal reelin expression, and hippocampal neurogenesis. Corticosterone produced dose-dependent increases in depression-like behavior and decreases in reelin expression, neurogenesis, and cell maturation regardless of mouse genotype. There were no differences between the vehicle-injected HRM and WTM in these measures. However, the effects of CORT on behavior, the number of reelin-positive cells in the subgranular zone or hilus, and hippocampal neurogenesis were more pronounced in the HRM than in the WTM, providing support for the idea that mice with impaired reelin signaling may be more vulnerable to the deleterious effects of glucocorticoids. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.
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PMID:Reelin as a putative vulnerability factor for depression: examining the depressogenic effects of repeated corticosterone in heterozygous reeler mice. 2084 64

Recent research has demonstrated that complex 'epigenetic' mechanisms, which regulate gene transcription without altering the DNA code, could play a critical role in the pathophysiology of psychiatric disorders. The present review summarizes recent evidence for the existence of sustained epigenetic mechanisms of gene regulation in several psychiatric disorders such as depression, schizophrenia and Rett syndrome. The gene transcriptions of the key molecules such as brain-derived neurotrophic factor (BDNF) or Reelin that play a role in on psychiatric disorders are regulated with histone modification or DNA methylation. Furthermore, one potential mechanism whereby stress can disrupt prenatal and/or neonatal development is through epigenetics, because the key issue of epigenetics is its long-term influence. In addition, we also found in the recent research that the epigenetic mechanism of gene regulation, especially histonedeacetylase, in the brain may be involved in the development of emotional resistance to stress stimuli. A better understanding of epigenetic regulation might provide new therapeutic avenues for disorders such as depression, schizophrenia, Rett syndrome and neurodevelopmental diseases.
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PMID:[Update on epigenetic regulation in pathophysiologies of stress-induced psychiatric disorders]. 2085 92

APOE is a major component of several lipoproteins. In addition to its role as a lipid transport protein APOE also serves a dual role as a glial derived, synaptic signalling molecule and thought to play an important role in synaptic plasticity and cognition. Polymorphisms within the APOE gene have been associated with the incidence of Alzheimer's disease. In light of the similarities in the cognitive deficits experienced in both Alzheimer's disease and schizophrenia as well as the comorbidity of depression in Alzheimer's disease, aberrant APOE signalling has been implicated in the pathologies of schizophrenia and mood disorders. The schizophrenia candidate gene, reelin, also shares common receptors with APOE, further supporting a role for APOE in the pathology of these disorders. This review will summarise the current understanding of the involvement of APOE and its receptors in the symptomatology and pathology of schizophrenia and mood disorders and the implications of this involvement for drug treatment.
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PMID:The neurobiology of APOE in schizophrenia and mood disorders. 2119 12


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